Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands

ABSTRACT

The present invention relates to novel indolin-2-one derivatives of formula:                    
     to the preparation and to the pharmaceutical compositions comprising them. 
     These compounds have an affinity for oxytocin receptors.

This application is a 371 of PCT/FR01/00980 Apr. 2, 2001.

A subject-matter of the present invention is novel indolin-2-onederivatives, a process for their preparation and the pharmaceuticalcompositions comprising them. These novel derivatives are powerful andselective ligands of the oxytocin receptors and can thus be used as anactive principle in pharmaceutical compositions, in particular in theobstetric or gynaecological field. Oxytocin (OT) is a hormone excretedby the neurohypophysis with a cyclic nonapeptide structure similar tothat of arginine vasopressin (AVP). The oxytocin receptors areessentially found on the smooth muscle of the uterus and on themyoedithelial cells of the mammary glands. Thus, oxytocin plays animportant role in parturition since it is involved in the contraction ofthe uterine muscle and in lactation. Furthermore, oxytocin receptors arealso located in other peripheral tissues and in the central nervoussystem; oxytocin can thus have effects in the cardiovascular, renal,endocrinal or behavioural fields.

Indolin-2-one derivatives have been disclosed in some patentapplications as ligands of the vasopressin receptors and possibly of theoxytocin receptors; mention may be made of Patent Applications WO93/15051, EP 636 608, EP 636 609, WO 95/18105, WO 97/15556 and WO98/25901. To date, no indolin-2-one derivative has been disclosed as apowerful and selective ligand of oxytocin receptors.

It has now been found that certain indolin-2-one derivatives arepowerful and selective ligands of oxytocin receptors.

Thus, according to one of its aspects, the present invention relates tonovel indolin-2-one derivatives in the form of a pure enantiomer or amixture of enantiomers of formula:

in which:

R₀ represents a group chosen from:

in which:

Z₁ represents a chlorine, bromine, iodine or fluorine atom or a(C₁-C₄)alkyl, (C₁-C₄)alkoxy or trifluoromethyl group;

Z₂ represents a hydrogen, chlorine, bromine, iodine or fluorine atom ora (C₁-C₄)alkyl, (C₃-C₅)cycloalkyl, (C₁-C₄)alkoxy, (C₃-C₅) cycloalkoxy or(C₁-C₄)polyfluoroalkyl group;

R₅ represents T₁W in which T₁ represents —(CH₂)_(m), it being possiblefor m to be equal to 0 or 1, and W represents a hydrogen atom or ahydroxycarbonyl (or carboxyl), (C₁-C₄)alkoxycarbonyl, 1,3-dioxolan-2-ylor 1,3-dioxan-2-yl group,

or else W represents an —NR₆R₇ group in which R₆ and R₇ represent,independently of one another, a hydrogen atom, a (C₁-C₄)alkyl group, a(C₁-C₄)alkylsulphonyl group or a phenylsulphonyl group in which thephenyl group can be mono-, di- or trisubstituted by Z₅; or else R₆ andR₇ form, with the nitrogen atom to which they are bonded, a morpholinylgroup optionally substituted by a (C₁-C₄)alkyl group or an oxo; or elseR₆ and R₇ form, with the nitrogen atom to which they are bonded, apiperazinyl group optionally substituted in the 4-position by a Z₃substituent; or else R₆ and R₇ form, with the nitrogen atom to whichthey are bonded, a pyrrolidinyl or piperidyl group, the saidpyrrolidinyl and piperidyl groups optionally being substituted by Z₄;

or else W represents an —NR₈COR₉ group in which R₈ represents a hydrogenatom or a (C₁-C₄)alkyl group and R₉ represents a hydrogen atom or a(C₁-C₄)alkyl, benzyl, pyridyl or phenyl group, it being possible for thesaid phenyl group to be mono-, di- or trisubstituted by Z₅; or else R₉represents an —NR₁₀R₁₁ group in which R₁₀ and R₁₁ represent,independently of one another, a hydrogen atom or a (C₁-C₄)alkyl [lacuna]or else R₁₀ and R₁₁ form, with the nitrogen atom to which they arebonded, a pyrrolidinyl, piperidyl or morpholinyl group optionallysubstituted by a (C₁-C₄)alkyl group; or else R₉ represents apyrrolidin-2-yl or -3-yl or piperid-2-yl, -3,-yl or -4-yl group, thesaid pyrrolidinyl and piperidyl groups optionally being substituted byZ₇; or else R₉ represents a —T₂—R₁₂ or —T₂—COR₁₂ group in which T₂represents —(CH₂)_(n)—, it being possible for n to be equal to 1, 2, 3and 4, and R₁₂ represents a (C₁-C₄)alkoxy or —NR₁₀R₁₁ group, R₁₀ and R₁₁being as defined above;

or else W represents a —CONR₁₃R₁₄ group in which R₁₃ represents ahydrogen atom or a (C₁-C₄) alkyl, (C₃-C₇) cycloalkyl,monofluoro(C₁-C₄)alkyl or polyfluoro(C₁-C₄)alkyl group and R₁₄represents a hydrogen atom, a (C₁-C₄)alkyl group, a phenyl groupoptionally substituted by Z₅, a —T₄—R₁₅ group in which T₄ represents—(CH₂)_(q), with q equal to 1, 2, 3 or 4, and R₁₅ represents a hydroxylgroup, a (C₁-C₄)alkoxy group, a (C₁-C₄)alkoxycarbonyl group, a(C₁-C₄)alkoxycarbonylamino group, a phenyl group optionally mono- ordisubstituted by Z₅, a pyrid-2-yl, -3-yl or -4-yl, or an —NR₁₆R₁₇ groupin which R₁₆ and R₁₇ represent, independently of one another, a hydrogenatom or a (C₁-C₄)alkyl [lacuna] or else R₁₆ and R₁₇ form, with thenitrogen atom to which they are bonded, a morpholinyl group optionallymono- or disubstituted by a (C₁-C₄)alkyl group or else R₁₆ and R₁₇ form,with the nitrogen atom to which they are bonded, a piperazinyl groupoptionally substituted in the 4-position by a Z₃ substituent or else R₁₆and R₁₇ form, with the nitrogen atom to which they are bonded, apyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidylgroups optionally being substituted by Z₅, it being understood that,when q=1, R₁₅ is other than hydroxyl, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonylamino or —NR₁₆R₁₇; or else R₁₃ and R₁₄ form, withthe nitrogen atom to which they are bonded, a morpholinyl groupoptionally mono- or disubstituted by a (C₁-C₄)alkyl group or apiperazinyl group optionally substituted in the 4-position by a Z₃substituent; or else R₁₃ and R₁₄ form, with the nitrogen atom to whichthey are bonded, an azetidinyl, pyrrolidinyl, piperidyl orhexahydroazepinyl group, the said pyrrolidinyl, piperidyl andhexahydroazepinyl groups optionally being mono- or disubstituted by Z₈;

or else W represents an OR₁₈ group in which R₁₈ represents a hydrogenatom or a (C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl or —T₃—R₁₉ group inwhich T₃ represents —(CH₂)_(p)—, it being possible for p to be equal to2 or 3, and R₁₉ is chosen from the hydroxyl, triphenylmethoxy or—NR₂₀R₂₁ groups in which R₂₀ represents a hydrogen atom or a(C₁-C₄)alkyl group and R₂₁ represents a hydrogen atom or a (C₁-C₄)alkyl,tetrahydrofuranylmethyl or tetrahydropyranylmethyl group, or else R₂₀and R₂₁ form,,with the nitrogen atom to which they are bonded, amorpholinyl group optionally mono- or disubstituted by a (C₁-C₄)alkylgroup or a piperazinyl group optionally substituted in the 4-position bya Z₃ substituent, or else R₂₀ and R₂₁ form, with the nitrogen atom towhich they are bonded, a pyrrolidinyl or piperidyl group, the saidpyrrolidinyl and piperidyl groups optionally being substituted by Z₅;

Z₃ represents a (C₁-C₄)alkyl, pyridyl, phenyl, (C₁-C₄)alkylcarbonyl or(C₁-C₄)alkoxycarbonyl group;

Z₄ represents an oxo, a fluorine atom, a hydroxyl, a (C₁-C₄)alkyl, abenzyl, an amino, a (C₁-C₄)alkylamino, a di(C₁-C₄)alkylamino, a(C₁-C₄)alkoxy, a (C₁-C₄)alkoxycarbonyl or a (C₁-C₄)alkoxycarbonylamino;

Z₅ represents a chlorine, bromine, iodine or fluorine atom, a hydroxylgroup, a (C₁-C₄)alkyl group or a (C₁-C₄)alkoxy group;

Z7 represents a fluorine atom, a hydroxyl group, a hydroxy(C₁-C₄)alkylgroup, a (C₁-C₄)alkyl [lacuna], a (C₁-C₄)alkoxy [lacuna] or a(C₁-C₄)alkylcarbonyl [lacuna];

Z₈ represents a fluorine atom or a hydroxyl, (C₁-C₄)alkyl,(C₃-C₆)cycloalkyl, benzyl, amino, (C₁-C₄)alkylamino,di(C₁-C₄)alkylamino, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkoxycarbonylamino,(C₃-C₆)cycloalkoxy, hydroxycarbonyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy or —CONR₂₃R₂₄ group in which R₂₃ and R₂₄represent, independently of one another, a hydrogen atom, a(C₁-C₄)alkyl, a monofluoro(C₁-C₄)alkyl or a polyfluoro(C₁-C₄)alkyl, orelse R₂₃ and R₂₄ form, with the nitrogen atom to which they are bonded,a pyrrolidinyl or piperidyl group, the said pyrrolidinyl or piperidylgroups optionally being substituted by Z₃ or a difluoromethylidene;

Z₆ represents a chlorine atom or a (C₁-C₄)alkyl or (C₁-C₄) alkoxy group;

R₁ represents a (C₁-C₄)alkyl group optionally comprising a double or atriple bond, a (C₁-C₄)alkoxycarbonyl group, a phenyloxycarbonyl group ora T₁—R₂₂ group in which T₁ is as defined above and R₂₂ represents ahydroxyl or (C₁-C₄)alkoxy group;

R₂ and R₄ represent, independently of one another, a hydrogen, chlorineor fluorine atom or a (C₁-C₄)alkyl or (C₁-C₄)alkoxy group;

R₃ represents a chlorine or fluorine atom or a (C₁-C₄)alkyl,(C₁-C₄)alkoxy, hydroxyl, (C₁-C₄)carbamoyl, (C₁-C₄)alkylcarbonylamino,nitro, cyano, trifluoromethyl, amino, (C₃-C₆)cycloalkylamino,(C₁-C₄)alkylamino, di(C₁-C₄) alkylamino, tri(C₁-C₄)alkylammonium A⁻, A⁻being an anion, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl,morpholin-4-yl or hexahydroazepin-1-yl group;

X and Y represent, independently of one another, a hydrogen, chlorine,bromine, iodine or fluorine atom or a (C₁-C₄)alkoxy or trifluoromethoxygroup; and to their pharmaceutically acceptable salts, their solvatesand their hydrates.

The term “alkyl” is understood to mean a saturated, linear or branched,monovalent hydrocarbonaceous radical.

The term “(C₁-C₄)alkyl” is understood to mean an alkyl radicalcomprising from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The term “alkylene” is understood to mean a saturated, linear orbranched, bivalent hydrocarbonaceous radical.

The term “alkoxy” is understood to mean an O-alkyl radical.

The term “anion A⁻” is understood to mean, for example, a Cl⁻, Br, I⁻ orCH₃SO₄ ⁻.

The term “di(C₁-C₄)alkylamino” is understood to mean an amino radicalsubstituted by two alkyl radicals which can be identical or different.In the same way, for tri(C₁-C₄)ammoniums, the alkyl radicals can beidentical or different.

The salts of the compounds according to the invention are preparedaccording to techniques which are well known to a person skilled in theart. The salts of the compounds of formula (I) according to the presentinvention comprise those with inorganic or organic acids, which makepossible suitable separation or crystallization of the compounds offormula (I), and pharmaceutically acceptable salts. Mention may be made,as appropriate acid, of: picric acid, oxalic acid or an optically activeacid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelicacid or a camphorsulphonic acid, and those which form physiologicallyacceptable salts, such as the hydrochloride, the hydrobromide, thesulphate, the hydrogensulphate, the dihydrogenphosphate, the maleate,the fumarate, the 2-naphthalenesulphonate or the para-toluenesulphonate,the hydrochloride being preferred.

When a compound according to the invention exhibits one or moreasymmetric carbons, the optical isomers of this compound form anIntegral part of the invention. When a compound according to theinvention exhibits stereoisomerism, for example of axial-equatorial orZ-E type, the invention comprises all the stereoisomers of thiscompound.

The present invention comprises the compounds of formula (I) in the formof pure isomers but also in the form of a mixture of isomers in anyproportion.

The compounds (I) are isolated in the form of pure isomers byconventional separating techniques: use may be made, for example, offractional recrystallizations of a salt of the racemate with anoptionally active acid or base, the principle of which is well known, orconventional chromatography techniques on a chiral or nonchiral phase.

The compounds of formula (I) above also comprise those in which one ormore hydrogen, carbon or halogen, in particular iodine, chlorine orfluorine, atoms have been replaced by their radioactive isotope, forexample tritium or carbon-14. Such labelled compounds are of use inresearch, metabolic or pharmacokinetic studies or in biochemical assaysas receptor ligand.

The functional groups possibly present in the molecule of the compoundsof formula (I) and in the reaction intermediates can be protected,either in permanent form or in temporary form, by protective groupswhich ensure unequivocal synthesis of the expected compounds. Theprotection and deprotection reactions are carried out according totechniques well known to persons skilled in the art. The term “temporaryprotective group for amines or alcohols” is understood to meanprotective groups such as those described in Protective Groups inorganic Synthesis, Greene T. W. and Wuts P. G. M., published by WileyIntersciences, 1999, and in Protecting Groups, Kocienski P. J., 1994,Georg Thieme Verlag.

Mention may be made, for example, of temporary protective groups foramines: benzyls, carbamates (such as tert-butyloxycarbonyl, which can becleaved in acidic medium, or benzyloxycarbonyl, which can be cleaved byhydrogenolysis); for carboxylic acids: alkyl esters (such as methyl,ethyl or tert-butyl esters, which can hydrolyse in basic or acidicmedium) and benzyl esters, which can be hydrogenolysed; for alcohols orfor phenols, such as tetrahydropyranyl, methyloxymethyl,methylethoxymethyl, tert-butyl and benzyl ethers; or for carbonylderivatives, such as linear or cyclic acetals, like, for example,1,3-dioxane-2-yl or 1,3-dioxolan-2-yl; and reference may be made to thewell known general methods described in the abovementioned ProtectiveGroups.

A person skilled in the art will be in a position to choose theappropriate protective groups. The compounds of formula (I) can compriseprecursor groups of other functional groups which are subsequentlygenerated in one or more other stages.

One family of compounds according to the invention is composed ofindolin-2-one derivatives in the form of a pure enantiomer or of amixture of enantiomers of formula:

in which:

R₀ represents

Z₁, Z₂, R₁, R₂, R₃, R₄, R₅, Y and X are as defined for (I), and theirpharmaceutically acceptable salts, their solvates and their hydrates.

According to another of its aspects, the invention relates to thecompounds of formula:

in which R₁ represents a methyl or hydroxyl group and R₀, R₂, R₃, R₄, Xand Y are as defined for (I); in the form of a pure enantiomer or of amixture of enantiomers, and their pharmaceutically acceptable salts,their solvates and their hydrates.

A subfamily of the compounds according to the invention is composed ofthe compounds of formula:

in which R₁ represents a methyl or hydroxyl group and R₀, R₃, R₄ and Xare as defined for (I); in the form of a pure enantiomer or of a mixtureof enantiomers, and their pharmaceutically acceptable salts, theirsolvates and their hydrates.

Another subfamily of the compounds according to the invention iscomposed of the compounds of formula:

in which R₁ represents a methyl or hydroxyl group and R₀ and R₃ are asdefined for (I); in the form of a pure enantiomer or of a mixture ofenantiomers, and their pharmaceutically acceptable salts, their solvatesand their hydrates.

Another subfamily of the compounds according to the invention iscomposed of the compounds of formula:

in which R₁ represents a methyl or hydroxyl group and R₀ is as definedfor (I); in the form of a pure enantiomer or of a mixture ofenantiomers, and their pharmaceutically acceptable salts, their solvatesand their hydrates.

Among these compounds of formula (I), (Ia), (Ib), (Ic) and (Id), thosein which R₀ represents the group:

in particular the group:

in which R₅ is as defined for (I), constitute another aspect of theinvention.

Among the latter compounds, those in which R₁ represents a methyl groupconstitute another aspect of the invention.

According to another of its aspects, the invention relates to thecompounds chosen from:5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one(Example 1);

5-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylamino)-2-methoxybenzyl]-3-methylindolin-2-one(Example 56);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}acetamide(Example 70);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methylbutanamide(Example 73);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}benzamide(Example 74);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}nicotinamide(Example 76);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-2-methoxyacetamide(Example 77);

Methyl3-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]anilino}-3-oxopropanoate(Example 78);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxypropanamide(Example 81);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide(Example 87);

N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethane-sulphonamide(Example 97);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-diethylbenzamide(Example 102);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-dimethylbenzamide(Example 109);

5-Chloro-3-[2-chloro-5-(1-piperidylcarbonyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one(Example 112);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethylbenzamide(Example 114);

5-Chloro-3-(2-chloro-5-{[2-(methoxymethyl)-1-pyrrolidinyl]carbonyl}phenyl)-1-(2,4-dimethoxy-benzyl)-3-methylindolin-2-one(Example 119);

5-Chloro-3-{2-chloro-5-[(2-methyl-1-piperidyl)-carbonyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one(Example 122);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-methylbenzamide(Example 124);

Methyl1-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl}-2-piperidine-carboxylate(Example 131);

5-Chloro-3-{2-chloro-5-[(4-hydroxy-1-piperidyl)-carbonyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methyl-indolin-2-one(Example 134);

5-Chloro-3-{2-chloro-5-[(2-methoxyethoxy)methyl]-phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one(Example 142);

5-Chloro-3-[2-chloro-5-(4-morpholinylmethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one(Example 148);

5-Chloro-3-(2-chloro-5-{[2-(4-morpholinyl)ethoxy]-ethyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one(Example 152);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-3-hydroxypiperidine(Example 194);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-3-hydroxypiperidine(Example 195);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-methoxypiperidine(Example 166);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-ethoxypiperidine(Example 167);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R,S)-2,6-dimethylpiperidine(Example 189);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxycarbonylpiperidine(Example 175);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-N,N-dimethyl-aminocarbonylpiperidine(Example 169);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-(N-methyl-N-2,2,2-trifluoroethylaminocarbonyl)piperidine(Example 170);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-pyrrolidinocarbonylpiperidine(Example 168);

1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(S)-2-methylpiperidine(Example 174);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-phenylethyl)benzamide(Example 185);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(4-pyridylmethyl)benzamidehydrochloride (Example 188);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide(Example 201);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyridylmethyl)benzamide(Example 200);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-methoxyethyl)benzamide(Example 184);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-dimethylaminoethyl)-benzamidehydrochloride (Example 177);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-morpholinoethyl)-benzamide(Example 178);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyrrolidinoethyl)-benzamidehydrochloride (Example 182);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-piperidinoethyl)-benzamidehydrochloride (Example 183);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-hydroxyethyl)benzamide(Example 198);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyrid-4-yl)ethyl]-benzamidehydrochloride (Example 179);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2,2,2-trifluoroethyl)-benzamide(Example 180);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N-(2,2,2-trifluoroethyl)-benzamide(Example 171);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-isopropylbenzamide(Example 187);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-(2-dimethylaminoethyl)-N-(2,2,2-trifluoroethyl)benzamidehydrochloride (Example 202);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-cyclohexylbenzamide(Example 192);

4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[3-(pyrid-4-yl)propyl]-benzamide(Example 204);

in the form of a pure enantiomer or of a mixture of enantiomers, and totheir pharmaceutically acceptable salts, their solvates and theirhydrates.

The compound of formula (I) can be prepared according to the followingScheme 1:

In this scheme, R₀, R₁, R₂, R₃, R₄, X and Y are as defined for (I) and,for (Ip), R′₀, R′₁, R′₂, R′₃, R′₄, X′ and Y′ respectively representeither R₀, R₁, R₂, R₃, R₄, X and Y as defined for (I) or a precursorgroup for R₀, R₁, R₂, R₃, R₄, X and Y, it being understood that R′₁ isother than hydrogen.

Another subject-matter of the present invention is a preparation processfor the compounds of formula (I), characterized in that:

a) a compound of formula:

in which X, Y, R₀ and R₁ are as defined for (I), is reacted in thepresence of a base with a halide of formula:

in which Hal represents a halogen atom and R₂, R₃ and R₄ are as definedfor (I);

b) or else, when R₁ represents an electrophilic group, the compound offormula:

in which R₀, R₂, R₃, R₄, X and Y are as defined for (I), is converted bythe action of a derivative R₁—Z, in which Z represents a leaving group,in the presence of a base;

c) or else, when R₁=OH, an isatin derivative of formula:

in which R₂, R₃, R₄, X and Y are as defined for (I), is reacted with anorganometallic derivative R₀—M or R₀MgHal, R₀ being as defined for (I),M being a metal atom and Hal being a bromine or iodine atom;

d) or else the compound of formula:

in which R′₀, R′₁, R′₂, R′₃, R′₄, X′ and Y′ respectively representeither R₀, R₁, R₂, R₃, R₄, X and Y as defined for (I) or a precursorgroup for R₀, R₁, R₂, R₃, R₄, X and Y, is subjected to a subsequenttreatment to convert any one of the R′₀, R′₁, R′₂, R′₃, R′₄, X′ and Y′groups to respectively R₀, R₁, R₂, R₃, R₄, X or Y as defined for (I),according to reactions well known to a person skilled in the art.

The reaction described in a) is preferably carried out with a compound(1) in which Hal=Cl or Br using, as base, a metal hydride, such assodium hydride, or an alkali metal alkoxide, such as potassiumtert-butoxide, in an anhydrous solvent, such as dimethylformamide ortetrahydrofuran.

In the reaction described in b), the term “leaving group” is understoodto mean, for example, a halogen atom, such as chlorine, bromine oriodine, or alternatively a sulphonic ester group, such aspara-toluenesulphonate. The compound (III) is preferably reacted with ahalide R₁-Hal, R₁ being as defined for (I) and Hal being a halogen atom,preferably an iodine atom, in the presence of a base; the reaction willbe carried out, for example, in the presence of a base, such as analkali metal alkoxide, for instance potassium tert-butoxide, in anethereal solvent, such as tetrahydrofuran, or alternatively in thepresence of a carbonate, such as sodium, potassium or caesium carbonate,in a solvent such as dimethylformamide or acetonitrile.

Advantageously, in the reaction described in c), the compound of formula(IV) is reacted with a magnesium derivative R₀Mg-Hal, R₀ being asdefined for (I) or (Ip) and Hal being a bromine or preferably iodineatom, or alternatively the compound (IV) is reacted with a derivativeR₀M in which M is preferably a lithium atom. This derivative R₀Li isobtained either by direct lithiation, for example by the action ofbutyllithium or lithium diisopropylamide according to Heterocycles,1993, 35(1), 151-169, or by a halogenlithium exchange reaction accordingto Organolithium Methods, Pergamon Press, New York, 1988 or J. Am. Chem.Soc., 1956, 2217. These reactions are preferably carried out in ananhydrous solvent, such as diethyl ether or tetrahydrofuran.

The conversion of the compound (Ip), the precursor of the compound (I),described in d) is carried out according to conventional techniques.

Furthermore, the compounds (I) can be obtained from another compound,(I)by conversion of one of the R₀, R₁, R₂, R₃, R₄, X or Y substituents, inparticular R₀, R₁ or R₃ substituents. For example:

the compounds (I) in which R₃=—NH₂ can be obtained by reduction of thecorresponding compounds (I) in which R₃=—NO₂, for example by the actionof hydrochloric acid in the presence of tin in an alcohol, such asethanol;

the compounds (I) in which R₃ represents a (C₁-C₄)alkylamino ordi(C₁-C₄)alkylamino group can be obtained from the correspondingcompounds (I) in which R₃=—NH₂ by a reductive amination reaction.Reference may be made to J. Org. Chem., 1996, 61, 3849-3862 and thereaction can be carried out by the action of a (C₁-C₄)alkyl aldehyde inthe presence of sodium triacetoxyborohydride or alternatively referencemay be made to J. Am. Chem. Soc., 1974, 96(25), 7812 and the reactioncan be carried out by the action of a (C₁-C₄)alkyl acid in the presenceof sodium borohydride. Use may also be made of conventional N-alkylationreactions, for example by reacting the amino group with a (C₁-C₄)alkylhalide in the presence of dimethylformamide and potassium carbonate;

the compounds (I) in which R₃ represents a (C₁-C₄)alkoxy can be obtainedfrom the corresponding compounds (Ip) in which R′₃=OH by a conventionalO-alkylation reaction, for example by the action of a (C₁-C₄)alkylhalide in the presence of dimethylformamide and of caesium or potassiumcarbonate;

the compounds (I) in which R₃ represents a (C₁-C₄)alkylcarbonylaminogroup can be obtained from the corresponding compounds (I) in whichR₃=—NH₂ by a conventional acylation, such as the action of a(C₁-C₄)alkyl acid chloride in the presence of a base, such astriethylamine, in a solvent, such as dichloromethane;

the compounds (I) in which R₃ represents a cyclic amine or amorpholin-4-yl can be obtained from the corresponding compounds (I) inwhich R₃=—NH₂ according to the method described in Tetrahedron, 1989,45(3), 629-636.

the compounds of formula (I) in which R₀ represents a group:

can be obtained from the corresponding compounds of formula (I) byconversion of the R₅ group according to conventional reactions, forexample alkylation, acylation, oxidation, reduction or aminationreactions, well known to a person skilled in the art.

The compounds (III) are prepared by dehalogenation of the compounds offormula:

in which R₀, R₂, R₃, R₄, X and Y are as defined for (I) and Halrepresents a chlorine, bromine or iodine atom, for example by the actionof a hindered lithium dialkylamide, such as lithium diisopropylamide(LDA), by analogy with the method described by N. Newcom et al. in J.Am. Chem. Soc., 1990, 5186-5193.

The compound (I′) is, for example, obtained by conversion of thecorresponding compound (I) in which R₁=OH by the action of a halogenatedderivative, for example of acid halide type. Mention may be made, aschlorinated derivative, of SOCl₂.

The compound (IV) is generally obtained by reaction of the compound (l)with the isatin derivative of formula:

in which X and Y are as defined for (I), under the same conditions asthose described above for the preparation of the compound (I) from thecompound (II). The isatin derivatives (2) are commercially availablecompounds or are prepared according to the methods described inTetrahedron Letters, 1998, 39, 7679-7682; Tetrahedron Letters, 1994, 35,7303-7306; J. Org. Chem., 1977, 42, 1344-1348 and Advances inHeterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, AcademicPress, New York, 1975, 18, 2-58.

The compounds (II) can be synthesized according to various methodsdisclosed in particular in Patent Applications EP 526 348 and WO95/18105.

Some routes for the production of the compounds (II) are illustrated inScheme 2:

The term “nucleophilic R₁” is understood to mean a (C₁-C₄) alkoxy group.

The compound (II) in which R₁ represents an electrophilic group, forexample a (C₁-C₄)alkyl group, can be prepared from the compounds offormula:

in which R₀, X and Y are as definded for (I), by reaction with aderivative R₁—Z in which Z represents a leaving group, under the sameconditions as those described above for the transformation of thecompound (III) to the compound (I).

The compound (V) is generally synthesized:

either by dehydroxylation of the corresponding compound (II) in whichR₁=OH by the action of tin chloride in acidic medium, according to themethod described in Tetrahedron, 1996, 52(20), 7003-7012, or by theaction of triethylsilane, according to Bioorganic and Medicinal Letters,1997, 7(10), 1255-1260;

or by a cyclization reaction in a strong acid medium, such as, forexample, sulphuric acid, of the compound of formula:

in which R₀, X and Y are as defined for (I), this compound (VII) itselfbeing obtained by a condensation reaction between an α-hydroxyaceticacid derivative of formula:

R₀ being as defined for (I), with an aminobenzene of formula:

in which X and Y are as defined for (I).

The compounds (3) are commercially available or are conventionallysynthesized.

The compounds of formula (VIII) are commercially available or aresynthesized according to methods well known to a person skilled in theart. Reference may in particular be made to J. Med. Chem., 1987, 30(8),1447.

Other reactions can also lead to the compounds (V). Mention may be madeof:

the Brunner reaction described in Tetrahedron, 1986, 42(15), 4267-4272:

the cyclization reaction in the presence of formic acid described in J.Chem. Soc. Perkin Trans., 1986, 1, 349-360:

the following cyclization reactions:

according to J. Am. Chem. Soc., 1985, 107(2), 435-443:

according to Tetrahedron, 1996, 52(20), 7003-7012.

The compounds (II) in which R₁ represents a (C₁-C₄)alkoxy group areobtained from the compounds of formula:

in which R₀, X and Y are as defined for (I) and Hal represents a halogenatom, for example a chlorine atom, by the action of the correspondingalcohol R₁H.

The compound (VI) is prepared from the corresponding compound (II) inwhich R₁=OH by reaction with thionyl chloride in the presence ofpyridine in dichloromethane.

The compounds (II) in which R₁=OH are generally prepared from thecorresponding isatin of formula:

in which X and Y are as defined for (I), according to the methoddescribed above for the preparation of the compounds (I) in which R₁=OHfrom the compounds (IV).

When R₁ does not represent a hydroxyl group, the compounds (II) can alsobe prepared according to Scheme 3 below:

In this Scheme 3, R₀, R₁, X and Y are as defined for (I), R₁ does notrepresent a hydroxyl group and M represents, for example, a lithium atomor MgHal, Hal being a halogen atom.

The transformation of the compound (X) to the compound (IX) to give thecompound (II) is carried out in particular according to the methoddescribed in J. Chem. Soc., 1957, 1928.

The benzyl halides (1) are known or are prepared according to knownmethods. Mention may be made, for example, of J. V. Rajanbabu, J. Org.Chem., 1986, 51, 1704-1712 and the publications cited in EP 636 609.

Generally, the halomethylbenzene derivatives (1) can be prepared by theaction of N-halosuccinimides on the corresponding methylbenzenederivatives and according to EP 229 566. The reaction is carried out ina solvent, such as carbon tetrachloride, in the presence of dibenzoylperoxide. A halomethylbenzene derivative can also be prepared from acorresponding hydroxymethylbenzene derivative by reaction withphosphorus tribromide in diethyl ether or by reaction with thionylchloride.

At any stage in the process, an intermediate compound of (IIp), (IIIp)or (IVp) type, in which at least one of the substituents is replaced byone of its precursor groups, can be formed intermediately. Thesecompounds (IIp), (IIIp) and (IVp) will be converted by conventionalreactions into (II), (III) and (IV) respectively. A person skilled inthe art will be in a position to adapt the abovementioned reactions tothe compounds (IIp), (IIIp) and (IVp).

The compounds according to the invention have formed the subject ofbiochemical and pharmacological studies. The affinity of the compoundsaccording to the invention for oxytocin receptors was determined in anin vitro binding test using the method described by J. Elands et al. inEur. Pharmacol., 1987, 147, 192-207. This method consists in studying invitro the displacement of a radioiodinated oxytocin analogue at theoxytocin receptors in a membrane preparation of human uterine oxytocinreceptors. The IC₅₀ values (concentration which inhibits 50% of thebinding of the radioiodinated oxytocin analogue to its receptors) arelow and vary from 10⁻¹⁰ to 10⁻⁶ M in the latter test.

The affinity of the compounds according to the invention for humanvasopressin V_(1a) receptors (method described by M. Thibonnier et al.in J. Biol. Chem., 1994, 269, 3304-3310), V_(1b) receptors (methoddescribed by T. Sugimoto et al. in J. Biol. Chem., 1994, 269,27088-27092) and V₂ receptors (method described by M. Birnbaumer et al.in Nature (Lond.), 1992, 357, 333-335) has also been studied. Thecompounds studied have little or no affinity for the V_(1a), V_(1b) andV₂ receptors. By way of indication, the compound of Example 1 exhibitsan IC₅₀ of less than 50 nM, the IC₅₀ values with respect to the V_(1a),V_(1b) and V₂ receptors being greater than 1 μM.

The agonist or antagonist nature of the compounds is determined in vitroin a test for the measurement of intracellular calcium with respect tocells expressing human oxytocin receptors according to the generaltechnique described in Am. J. Physiol., 268 (Heart Circ. Physiol., 37),1995, H404-H410.

When the compounds according to the invention behave as antagonists,their IC₅₀ is advantageously between 0.5 μM and 0.5 nM. By way ofexample, the dextrorotatory enantiomer of Example 1 is an antagonistwith an IC₅₀ of 3.2±1.9 nM.

The compounds according to the invention, powerful and selective ligandsof oxytocin receptors, are particularly advantageous in the preventionand/or treatment of oxytocin-dependent disorders. The compoundsaccording to the present invention can either mimic or inhibit theeffects of oxytocin.

They will be particularly advantageous in cicatrization, in analgesiaand anxiolysis (prevention of pain and anxiety), depression,schizophrenia, autism, obsessive compulsive syndrome, in maternalbehaviour (facilitation of mother-child recognition and acceptance) andsocial behaviour, memory, regulation of food and drink intake,dependence on drugs, weaning and sexual motivation. They can beadvantageously used in disorders of the urogenital sphere, in particularin the obstetric and gynaecological fields, in particular as uterinerelaxant or tocolytic agent or for controlling contractions of theuterus before pregnancy has arrived at term, for controlling prenatallabour or for controlling preparatory labour for the purpose of acaesarean delivery, for solving problems of sterility or fertility,controlling births (in particular veterinary use), controlling oestrus,the halting of breast feeding, weaning, or embryo transfer andimplantation; treating endometriosis, dysmenorrhoea and urinary stressor urgency incontinence, benign prostate hypertrophy and erectiledysfunctions, hypertension, hyponatraemia, cardiac insufficiency,atherosclerosis or angiogenesis, and regulating the storage of fat bythe adipocyte.

Furthermore, given the role of oxytocin in controlling luteinizinghormone (J. J. Evans, J. Endocrin., 1996, 151, 169-174), the compoundsof the invention can be used to induce contraception.

Furthermore, the compounds according to the invention can be used fortheir antitumour effects in oxytocin-secreting tumours, in particularbreast and prostate cancers.

The use of the compounds according to invention for the preventionand/or the treatment of the abovementioned conditions and for thepreparation of medicaments intended to treat these conditions forms anintegral part of the invention.

Another subject-matter of the present invention is thus pharmaceuticalcompositions comprising a compound according to the invention or apharmaceutically acceptable salt, solvate or hydrate of the latter andsuitable excipients. The said excipients are chosen according to thepharmaceutical form and the method of administration desired: oral,sublingual, subcutaneous, intramuscular, intravenous, topical,intratracheal, intranasal, transdermal, rectal or intraocular. Thepharmaceutical compositions are prepared according to techniques knownto a person skilled in the art.

In order to obtain, the desired prophylactic or therapeutic effect, eachunit dose can comprise from 0.5 to 1 000 mg, preferably from 1 to 500mg, of active ingredients in combination with a pharmaceutical vehicle.This unit dose can be administered 1 to 5 times daily, so as toadminister a daily dosage of 0.5 to 5 000 mg, preferably from 1 to 2 500mg.

The compounds according to the invention can also be used for thepreparation of compositions for veterinary use intended to regulatebirths.

The compounds according to the invention can also be used for thepreparation of cosmetic compositions. These formulations can be providedin the form of a cream for topical use and will be intended to controllipolysis.

The compositions of the present invention can comprise, in addition tothe products of formula (I) above or their pharmaceutically salts,solvates and hydrates, [lacuna] and for example active principles whichmay be of use in the treatment of the disorders or conditions indicatedabove. Thus, another subject-matter of the present invention ispharmaceutical compositions comprising several active principles incombination, one of which is a compound according to the invention. Inparticular, the present invention relates to pharmaceutical compositionscomprising a compound according to the invention, an antagonist ofoxytocin receptors, with a V_(1a) antagonist compound. This type ofcomposition will be of particular use in the treatment of dysmenorrhoeaor endometriosis or the control of premature labour and for controllingpreparatory labour for the purpose of a caesarean delivery.

Another subject-matter of the invention is products comprising anantagonist of oxytocin receptors as defined above and an antagonist ofvasopressin V_(1a) receptors for simultaneous or separate use or usespread out over time in the treatment of dysmenorrhoea or endometriosisor the control of premature labour and for controlling preparatorylabour for the purpose of a caesarean delivery.

The following PREPARATIONS and EXAMPLES illustrate the inventionwithout, however, limiting it.

The nuclear magnetic resonance spectra were recorded in deuteratedchloroform, unless otherwise mentioned, at 200 MHz and the chemicalshifts are expressed in ppm. The abbreviations used below are asfollows: s=singlet; m=multiplet; d=doublet, t=triplet; q=quintet.

All the compounds according to the invention have formed the object oforganic elemental analysis carried out by combustion at 1 000° C. in thepresence of oxygen using a balance of Supermicro S4 Sartorius type andan elemental analyser of EA 1108 type. The percentage analyses of theelements carbon, hydrogen, nitrogen and sulphur obtained are inagreement with the theoretical results expected.

PREPARATIONS Preparation 1 N-(4-Chlorophenyl)-2-oxopropionamide,Compound XI.1

26.3 g of 4-chlorophenylamine in 150 ml of dichloromethane and 35 ml oftriethylamine are added, at −60° C., to 22 g of 2-oxopropionyl chloride(prepared according to Synthesis, 1975, 163-164 from 2-oxopropionic acidand 1,1-dichlorodimethyl ether) in 350 ml of dichloromethane. Thereaction mixture is stirred at −60° C. for 2 hours and then 200 ml of a0.15N aqueous hydrochloric acid solution and 500 ml of dichloromethaneare added at −30° C. The organic phase is extracted, washed with a 0.25Naqueous hydrochloric acid solution and dried over sodium sulphate. Thesolvents are evaporated under reduced pressure and the residue obtainedis crystallized from dichloromethane;

M.p.=151° C.

Preparation 22-(2-Chloro-4-fluorophenyl)-N-(4-chlorophenyl)-2-hydroxypropionamide,Compound IX.1

0.18 g of magnesium and 2.57 g of 2-chloro-4-fluoro-1-iodobenzene arestirred at reflux in 30 ml of diethyl ether. The mixture thus obtainedis added at −60° C. to 0.99 g of compound XI.1 in 9 ml oftetrahydrofuran. The reaction mixture is stirred at 20° C. for 2 hoursand then a saturated aqueous NH₄Cl solution is added. Extraction iscarried out with ethyl acetate, the organic phase is dried over Na₂SO₄and the solvents are evaporated under reduced pressure. The residueobtained is purified by chromatography on a column of silica gel,elution being carried out with a 1/1 (v/v) cyclohexane/dichloromethanemixture and then a 99/1 (v/v) dichloromethane/methanol mixture. Thesolid thus isolated is crystallized from diisopropyl ether; M.p. 167° C.

The following compounds are prepared in the same way:

N-(4-Chlorophenyl)-2-(2,5-dimethoxyphenyl)-2-hydroxypropionamide,compound IX.2; M.p. 145° C.

N-(4-Chlorophenyl)-2-(2-chloro-4-methylphenyl)-2-hydroxypropionamide,compound IX.3; M.p. 116° C.

N-(4-Chlorophenyl)-2-(2-chloro-5-methylphenyl)-2-hydroxypropionamide,compound IX.4; M.p. 147° C.

N-(4-Chlorophenyl)-2-(2-chloro-5-fluorophenyl)-2-hydroxypropionamide,compound IX.5; M.p. 171° C.

Preparation 3 (2-Chlorophenyl)-N-(4-chlorophenyl)hydroxyacetamide,Compound VII.1

A mixture of 60 g of (2-chlorophenyl)hydroxyacetic acid and 41 g of4-chlorophenylamine in 300 ml of 1,2-dichlorobenzene is heated to 200°C. The setup comprises a Dean and Stark apparatus and thus the waterformed is removed during the reaction. Approximately 150 ml of solventare distilled off and the expected compound is crystallized at 20° C.The solid obtained is rinsed with diisopropyl ether; M.p.=120° C.

In the same way, (2-chlorophenyl)-N-(4-methoxyphenyl)hydroxyacetamide,compound VII.2, is prepared from 4-methoxyphenylamine; M.p.=130° C.

In the same way,(2-chloro-4-fluorophenyl)-N-(4-chlorophenyl)hydroxyacetamide, compoundVII.3, is prepared from (2-chloro-4-fluorophenyl)hydroxyacetic acid(synthesized according to J. Med. Chem., 1987, 30 (8), 1447, from2-chloro-4-fluorobenzaldehyde and bromoform); M.p.=136° C.

Preparation 4 5-Chloro-3-(2-chlorophenyl)indolin-2-one, Compound V.1

A solution of 263 ml of 95% sulphuric acid and 100 ml of 20% oleum isprepared at 10° C. This solution is stirred with 74 g of compound VII.1for 2 hours at 40° C. The reaction mixture is subsequently cooled andthen poured onto ice-cold water. The precipitate obtained is filteredoff and then washed with 1 000 ml of water. The solid is dissolved indichlorormethane and the solution thus obtained is washed successivelywith a saturated aqueous sodium hydrogencarbonate solution and withwater and then dried over Na₂SO₄. The solvents are evaporated underreduced pressure and then the solid obtained is washed with diethylether; M.p.=201° C.

Compound V.2 below is prepared in the same way:

5-Chloro-3-(2-chloro-4-fluorophenyl)indolin-2-one, compound V.2.

M.p.=221° C.

Preparation 5 5-Methoxy-3-(2-chlorophenyl)indolin-2-one, Compound V.3

20.1 g of 2-(2-chlorophenyl)-N-(4-methoxyphenyl)-2-hydroxyacetamide,compound VII.2, are added to a mixture of polyphosphoric acid, obtainedfrom 65 ml of 85% phosphoric acid and 130 g of phosphorus pentoxide, ata temperature of 50° C. and then the reaction mixture is maintained atthis temperature for 6 hours. After cooling, treatment is carried outwith an aqueous sodium hydrogencarbonate solution until a pH of 5 isobtained. Extraction is carried out with ethyl acetate. The organicphase is washed with water and then dried over anhydrous sodiumsulphate. The solvent is partially evaporated under reduced pressure andthe expected product is filtered off; M.p.=179° C.

Preparation 6 5-Chloro-3-(2-chlorophenyl)-3-methylindolin-2-one,Compound II.1

18.2 g of potassium tert-butoxide are added at −40° C. to a solution of15 g of compound V.1 in 240 ml of tetrahydrofuran. The reaction mixtureis stirred at 0° C. for 5 minutes and then a solution of 3.7 ml ofmethyl iodide in 80 ml of tetrahydrofuran is added at −60° C. Once thetemperature of the reaction mixture has returned to 0° C., 100 ml of asaturated aqueous ammonium chloride solution are added and extraction iscarried out with ethyl acetate. The organic phase is washed with waterand then dried over anhydrous sodium sulphate. The solvents areevaporated under reduced pressure. The solid obtained is purified bychromotagraphy on a column of silica gel, elution being carried out witha 1/9 (v/v) ethyl acetate/cyclohexane mixture. The solid obtained iscrystallized from n-pentane; M.p.=185° C.

Compounds II.2 to II.6 below are prepared in the same way.

TABLE 1 Compound R₀ R₁ M.p.; ° C. II.2

—CH₂—C≡CH 219 II.3

—CH₂—CH═CH₂ 218 II.4

—CH₂CH₃ 198 II.5

—CH₂CH₂CH₃ 218 II.6

—CH₃ 189

5-Methoxy-3-(2-chlorophenyl)-3-methylindolin-2-one, compound II.7, isprepared according to the same procedure from5-methoxy-3-(2-chlorophenyl)indolin-2-one; M.p.=176° C.

Preparation 75-Chloro-3-(2-chloro-4-fluorophenyl)-3-methylindolin-2-one, CompoundII.6

Compound II.6, described above, can also be prepared as follows:

0.3 g of compound IX.1 and a solution, prepared beforehand, of 5.3 g ofphosphorus pentoxide in 3 ml of an 85% aqueous phosphoric acid solutionare heated to 150° C. for 5 hours. The reaction mixture is poured ontoice, a saturated aqueous potassium carbonate solution is added andextraction is carried out with ethyl acetate. The organic phase thusobtained is dried over anhydrous sodium sulphate. The solvents areevaporated under reduced pressure. The solid obtained is crystallizedfrom n-pentane; M.p.=189° C.

The compound 5-chloro-3-(2,5-dimethoxyphenyl)-3-methylindolin-2-one,compound II.8;

is prepared in the same way.

M.p.=163° C.

Preparation 85-Chloro-3-[2-chloro-5-(4-methyl-1-piperazinyl)phenyl]-3-methylindol-2-one,Compound II.9

The mixture composed of 0.5 g of compound II.6, 2.5 ml of dimethylsulphoxide, 3.6 ml of N-methylpiperazine, 1 g of sodium carbonate and0.1 g of cuprous iodide is heated at 120° C. for 24 hours. Afterreturning to room temperature, the salts are filtered off through talcand the precipitate is rinsed with dimethyl sulphoxide and then with 60ml of ethyl acetate. The filtrate is washed with 40 ml of water and theorganic phase is dried over anhydrous sodium sulphate. The solvents areevaporated under reduced pressure and the residue is purified bychromatography on a column of silica gel, elution being carried out withdichloromethane. The expected product is isolated after taking up thesolid residue in diisopropyl ether and then filtering; M.p.=155° C.

Preparation 95-Chloro-3-(2-chloro-4-fluorophenyl)-3-hydroxyindolin-2-one, CompoundII.10

0.44 g of a 60% dispersion of sodium hydride in oil is added at −40° C.to a cooled suspension of 2 g of 5-chloroindolin-2,3-dione in 60 ml oftetrahydrofuran and the reaction mixture is stirred at 0° C. for 15minutes. 0.45 g of magnesium and 4.23 g of2-chloro-4-fluoro-1-iodobenzene in 18 ml of diethyl ether are stirred atreflux for 3 hours. The solution thus obtained is slowly added at −60°C. to the reaction mixture. The reaction mixture is stirred for 30minutes at 20° C. and a saturated aqueous ammonium chloride solution isadded. Extraction is carried out with ethyl acetate, the organic phaseis dried over anhydrous sodium sulphate and the solvents are evaporatedunder reduced pressure. The residue obtained is purified bychromatography on a column of silica gel, elution being carried out withdichloromethane and then with a 95/5 (v/v) dichloromethane/methanolmixture. The solid obtained is crystallized from n-pentane; M.p.=239° C.

In the same way,5-chloro-3-(2,5-dimethoxyphenyl)-3-hydroxyindolin-2-one, compound II,11;

is prepared from 1-bromo-2,5-dimethoxybenzene.

M.p.=221° C.

Preparation 10 3,5-Dichloro-3-(2,5-dimethoxyphenyl)indolin-2-one,Compound VI.1

0.8 ml of thionyl chloride is added, at a temperature of less than 20°C., to 3 g of compound II.11 in the presence of 1.2 ml of pyridine in 50ml of dichloromethane and then the reaction mixture is stirred for onehour. The reaction mixture is washed with water and dried over anhydroussodium sulphate. The solvents are evaporated under reduced pressure andthen the residue is chromatographed on a column of silica gel, elutionbeing carried out with dichloromethane. M.p.=157° C.

The following compounds are prepared in the same way:

3,5-Dichloro-3-(2-chlorophenyl)indolin-2-one, compound VI.2.

M.p.=190° C.

3,5-Dichloro-3-(2-chloro-4-fluorophenyl)indolin-2-one, compound VI.3.

M.p.=87° C.

Preparation 11 5-Chloro-3-(2,5-dimethoxyphenyl)-3-methoxyindolin-2-one,Compound II.11

0.4 g of compound VI.1 in the presence of 25 ml of methanol in 50 ml oftetrahydrofuran is maintained at reflux for 3 hours. The solvents areevaporated under reduced pressure. M.p.=180° C.

The following compounds are prepared in the same way:

5-Chloro-3-(2-chlorophenyl)-3-methoxyindolin-2-one, compound II.12.

M.p.=179° C.

5-Chloro-3-(2-chloro-4-fluorophenyl)-3-methoxyindolin-2-one, compoundII.13.

M.p.=82° C.

Preparation 12 5-Chloro-1-(2,4-dimethoxybenzyl)indolin-2,3-dione,Compound IV.1

(IV.1.):R₂=H; R₃=4-OCH₃; R₄=2-OCH₃; X=5-Cl; Y=H

a) 0.25 ml of phosphorus tribromide is added at −50° C. to a suspensionof 1.45 g of 2,4-dimethoxyphenylmethanol in 25 ml of diethyl ether. Thesolution thus obtained is allowed to return to a temperature of 0° C.

b) 2 g of potassium tert-butoxide are added at −60° C. to a suspensionof 1.3 g of 5-chloroindolin-2,3-dione in 50 ml of tetrahydrofuran. Thereaction mixture is stirred at 0° C. for 5 minutes and then the solutionprepared in a) is added at −60° C. The reaction mixture is stirred atroom temperature for 16 hours and then the solvents are evaporated underreduced pressure. The residue obtained is purified by chromatography ona column of silica gel, elution being carried out with acyclohexane/dichloromethane mixture varying from 8/2 to 2/8 (v/v). Thesolid obtained is crystallized from toluene; M.p.=175° C.

The following compounds are prepared in the same way:

5-Chloro-1-(4-chloro-2-methoxybenzyl)indolin-2,3-dione, Compound IV.2.

M.p.=136° C.

5,7-Dichloro-1-(2,4-dimethoxybenzyl)indolin-2,3-dione, Compound IV.3.

M.p.=171° C.

5-Fluoro-1-(2,4-dimethoxybenzyl)indolin-2,3-dione, Compound IV.4.

M.p.=163° C.

1-(2,4-Dimethoxybenzyl)indolin-2,3-dione, Compound IV.5.

M.p.=142° C.

Example 15-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

a) 0.48 ml of phosphorus tribromide is added at −50° C. to a suspensionof 2.6 g of 2,4-dimethoxyphenylmethanol in 45 ml of diethyl ether. Thesolution thus obtained is allowed to return to a temperature of 0° C.

b) 1.2 g of potassium tert-butoxide are added at −40° C. to 3 g ofcompound II.1 in solution in 90 ml of tetrahydrofuran and then thereaction mixture is stirred until the temperature has returned to 0° C.The reaction mixture is subsequently cooled to −60° C. and the solutionprepared in a) is added. The reaction mixture is stirred at 20° C. for 2hours, 50 ml of water are added and extraction is carried out with ethylacetate. The organic phases are dried over sodium sulphate and thesolvents are evaporated under reduced pressure. The solid obtained iscrystallized from diisopropyl ether; M.p.=179° C.

This compound, in the racemic form, is then separated by chromatographyon a Chiralpak® AD column from Daicel, elution being carried out with a98/2 (v/v) 2-methylpentane/ethanol mixture.

The dextrorotatory enantiomer: M.p.=92° C.; [α]_(D) ^(23.5)=+39° (c=1,CH₃OH), and its antipode are thus isolated.

Example 25-Methoxy-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

The compound of Example 2 is prepared according to the same procedurefrom 5-methoxy-3-(2-chlorophenyl)indolin-2-one, compound II.7;

M.p.=133° C.

Example 35-Chloro-3-(2-chlorophenyl)-1-[4-(1,1-dimethylethoxy)-2-methoxybenzyl]-3-methylindolin-2-one

a) Preparation of [4-(1,1-dimethylethoxy)-2-methoxy]phenylmethanol

Preparation of methyl [4-(1,1-dimethylethoxy)-2-methoxy]benzoateaccording to J. Org. Chem., 1986, 51, 111-113.

0.25 ml of trifluoromethanesulphonic acid is added at −70° C. to 6.2 gof methyl 4-hydroxy-2-methoxybenzoate (according to J. Med. Chem., 1985,28, 717-727, from commercial methyl 2,4-dihydroxybenzoate) in 60 ml ofdichloromethane and then 25 ml of 2-methylpropene, condensed beforehandat −20° C. and degassed by natural rewarming, are added by means of adip pipe. After stirring for 24 hours at a temperature of between −30and −70° C., 0.5 ml of triethylamine is added to the reaction mixture.The solvents are evaporated under reduced pressure and the residue istaken up in ethyl acetate and washed with a dilute sodium bicarbonatesolution. The separated organic phase is dried over anhydrous sodiumsulphate and the solvents are evaporated under reduced pressure. Theexpected product is isolated, purification being carried out bychromatography on a column of silica gel, elution being carried out withcyclohexane.

¹H NMR: 7.75 (d, 1H), 6.62-653 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 1.40(s, 9H).

According to J. Chem. Soc. Perkin Trans., 1991, 3291-3294.

15.90 ml of a 2M solution of LiBH₄ in tetrahydrofuran are added to 2.5 gof the preceding compound obtained in a) in 25 ml of toluene. Thereaction mixture is heated at 100° C. for 45 minutes. At approximately20° C., the reaction mixture is poured onto a water/ice mixture and theaqueous phase is extracted with ethyl acetate. After separating bysettling, the aqueous phase is extracted with ethyl acetate. The organicphases are combined and dried over anhydrous sodium sulphate and thenthe solvents are evaporated under reduced pressure.

¹H NMR: 7.10 (d, 1H), 6.59-6.50 (m, 2H), 4.61 (d, 2H), 3.81 (s, 3H),2.20 (t, 1H), 1.34 (s, 9H).

b) The compound of Example 3 is prepared according to the same procedureas for Example 1; M.p.=131° C.

Example 45-Chloro-3-p(2-chorophenyl)-1-[4-(-methylethoxy)-2-methoxybenzyl]-3-methylindolin-2-one

a) Preparation of [4-(1-methylethoxy)-2-methoxy]phenylmethanol.

Preparation of methyl [4-(1-methylethoxy)-2-methoxy]benzoate accordingto Synthesis, 1988, 712.

2.86 g of caesium carbonate and then 1.28 ml of 2-iodopropane are addedat 0° C. to 0.8 g of methyl 4-hydroxy-2-methoxybenzoate in 20 ml ofdimethylformamide. The reaction mixture is stirred at 20° C. for 2hours, 50 ml of water are then added and extraction is carried out withethyl acetate. The organic phase is washed with water and then driedover anhydrous sodium sulphate. The solvents are evaporated underreduced pressure.

¹H NMR: 7.81 (d, 1H), 6.47-6.42 (m, 2H), 4.69-4.51 (m, 1H), 3.85 (s,3H), 3.83 (s, 3H), 1.33 (d, 6H).

[4-(1-Methylethoxy)-2-methoxyphenyl]methanol is prepared according tothe method described above in Example 3 for the transformation of methyl[4-(1,1-dimethylethoxy)-2-methoxy]benzoate into[4-(1,1-dimethylethoxy)-2-methoxy]phenylmethanol.

b) The compound of Example 4 is prepared according to the proceduredescribed for Example 1;

M.p.=158° C.

Examples 5 to 17 below are prepared according to the procedure describedfor Example 1.

Example 55-Chloro-3-(2-chlorophenyl)-1-(2-methoxy-4-nitrobenzyl)-3-methylindolin-2-one

M.p.=179° C.

Example 65-Chloro-1-(2,4-dimethoxybenzyl)-3-(2,5-dimethoxyphenyl)-3-methylindolin-2-one

M.p.=140° C. (0.3 H₂O)

TABLE 2 (I)

M.p.; ° C.; EXAMPLE R₁ salt, hydrate 7 —CH₂—C≡CH 135 8 —CH₂—CH═CH₂ 117 9—CH₂CH₃ 102 10 —CH₂CH₂CH₃ 119

TABLE 3 (I)

EXAMPLE R₀ R₄ M.p.; ° C. 11

2-OCH₃ 155 12

3-OCH₃ 150 13

2-OCH₃ 121 14

2-OCH₃ wax

TABLE 4 (I)

EXAMPLE R₀ M.p.; ° C. 15

112 16

168 17

113

Example 185-Chloro-3-(2-chloro-4-fluorophenyl)-1-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one

This compound can be prepared from compound II.10 according to the sameprocedure as for Example 1 or else according to the method below:

0.87 ml of 2-chloro-4-fluoro-1-iodobenzene and 0.09 g of magnesium in 15ml of diethyl ether are stirred at reflux for 1 hour. 0.75 g of compoundIV.1, in partial solution in 15 ml of tetrahydrofuran, is added at −40°C. The reaction mixture is stirred for 2 hours at 20° C. and then asaturated aqueous ammonium chloride solution is added. Extraction iscarried out with ethyl acetate, the organic phase is dried overanhydrous sodium sulphate and then the solvents are evaporated underreduced pressure. The residue obtained is purified by chromatography ona column of silica gel, elution being carried out with a 1/1 (v/v)cyclohexane/dichloromethane mixture. The solid obtained is crystallizedfrom cyclohexane; M.p.=177° C.

This compound, in the racemic form, is separated by chromatography on aChiralpak® AD column from Daicel, elution being carried out with a 9/1(v/v) 2-methylpentane/ethanol mixture.

The dextrorotatory enantiomer:[α]_(D)^(20.5) = +63^(∘)  (c = 1, CH₃OH),

and its antipode are thus isolated.

Example 195-Chloro-3-(2-chloro-5-methoxymethoxymethylphenyl)-1-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one

a) Preparation of 2-chloro-1-iodo-5-hydroxymethylbenzene according to J.Org. Chem., 1991, 56, 5964-5965, from the corresponding commercialbenzoic acid.

5.02 g of sodium borohydride are added portionwise and then 14.6 g ofiodine, in solution in 50 ml of tetrahydrofuran, are added very slowlyto 25 g of 4-chloro-3-iodobenzoic acid in solution in 200 ml oftetrahydrofuran at 0° C. The reaction mixture is stirred for 2 hours atroom temperature and then at 35° C. for 30 minutes. Hydrolysis iscarried out at 10° C. with a 0.5N hydrochloric acid solution andextraction is carried out with ethyl acetate. The organic phase isseparated by settling and then treated with an aqueous sodium bisulphitesolution and then with water. The organic phase is dried over anhydroussodium sulphate and the solvents are evaporated under reduced pressure.The expected compound is obtained by distillation;

B.p.=109° C. under 3 Pa.

b) Preparation of 2-chloro-1-iodo-5-methoxymethyleneoxymethylbenzeneaccording to Synthesis, 1985, 74.

1.5 ml of para-toluenesulphonic acid monohydrate and 1.4 g of lithiumbromide are added to 24.45 g of the preceding compound in 100 ml ofdimethoxymethane. The reaction mixture is stirred at 35° C. for 4 hoursand then for 2 hours at reflux. Hydrolysis is carried out at roomtemperature with a dilute aqueous sodium bicarbonate solution andextraction is carried out with diethyl ether. The organic phase iswashed with water and dried over anhydrous sodium sulphate and thesolvents are evaporated under reduced pressure. The expected product isobtained by distillation; B.p.=108° C. under 1.9 Pa.

c) The compound of Example 19 is prepared according to the proceduredescribed for Example 18;

M.p.=142° C.

Example 20 Methyl4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]benzoate

45.2 ml of a 1.6M solution of n-butyllithium in hexane, diluted in 200ml of tetrahydrofuran and cooled to −90° C., are slowly added to 10.72 gof methyl 4-chloro-3-iodobenzoate (prepared by esterification of thecorresponding commercial acid; M.p.=56° C.) in 200 ml of tetrahydrofurancooled to −100° C. The reaction mixture is stirred at −95° C. for 20minutes and then the solution, cooled to −70° C., of 10 g of compoundIV.1 in 600 ml of tetrahydrofuran is added. After returning to roomtemperature, hydrolysis is carried out with 200 ml of a saturatedammonium chloride solution, the solvents are partially evaporated underreduced pressure, extraction is carried out with ethyl acetate, theorganic phase is dried over anhydrous sodium sulphate and then thesolvents are evaporated under reduced pressure. The residue obtained iswashed with diethyl ether, filtered off and then dried at 5° C. underreduced pressure; M.p.=236° C.

Example 213-(5-Amino-2-chlorophenyl)-5-chloro-1-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one

a) Preparation of4-chloro-3-bromo-N,N-(tetramethyl-ethylene)disilylaniline

A mixture composed of 3.3 g of 3-bromo-4-chloroaniline, 3.72 g ofbis(dimethylaminodimethyl-silyl)ethylene, obtained according toTetrahedron Letters, 1984, 25 (12), 1253-1254, and 0.03 g of zinc iodideis heated at140° C. for 5 hours under an argon stream. The expectedproduct is distilled; B.p.=105° C. under 37 Pa.

b) The compound of Example 21 is prepared according to the sameprocedure described for Example 20, purification being carried out bychromatography on a column of silica gel, elution being carried out witha 99/1 (v/v) dichloromethane/methanol mixture;

M.p.=133° C.

The compounds of Examples 22 to 31 below are prepared in the same way asfor Example 18:

TABLE 5 (I)

M.p; ° C.; salt, EXAMPLE R₀ hydrate 22

156 23

185 24

190 0.7 H₂O 25

207 26

198 27

186 28

196 29

199 30

161 31

148

Example 325,5-Chloro-1-(2,4-dimethoxybenzyl)-3-[5-(1,3-dioxolan-2-yl)-2-methoxyphenyl]-3-hydroxyindolin-2-one

a) Preparation of 2-(3-bromo-4-methoxyphenyl)-1,3-10 dioxolane accordingto J. Med. Chem., 1990, 33(3), 972.

A mixture composed of 5 g of 3-bromo-para-anisaldehyde, 5 ml of ethyleneglycol, 0.088 g of para-toluenesulphonic acid and 125 ml of toluene isheated at reflux for 1 hour 30 minutes in a reactor equipped with a Deanand Stark apparatus. The reaction mixture is poured at room temperatureonto 50 ml of water, extraction is carried out with diethyl ether andthe organic phase is dried over anhydrous sodium sulphate. The solventsare evaporated under reduced pressure. The oil obtained is purified bychromatography on a column of silica gel, elution being carried out withan 8/2 (v/v) cyclohexane/ethyl acetate mixture. The expected product isobtained after distillation under reduced pressure; B.p.=128° C. under 5Pa.

b) The compound of Example 32 is prepared from the preceding compoundaccording to the procedure described for Example 18; M.p.=140° C.

Example 335-Chloro-1-(2,4-dimethoxybenzyl)-3-{5-[(dimethylamino)-methyl]-2-methoxyphenyl}-3-hydroxyindolin-2-one

a)3-[5-Chloro-1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]-4-methoxybenzaldehyde,obtained by deprotection of the compound of Example 32 in acidic mediumaccording to J. Chem. Soc. Chem. Commun., 1987, 1351.

The mixture composed of 0.55 g of the compound of Example 32, 5 ml ofacetone, 2.5 ml of water and 0.22 ml of 1N hydrochloric acid is broughtto 30° C. for 2 hours with stirring. The reaction mixture is neutralizedat room temperature with an aqueous sodium bicarbonate solution andextraction is carried out with ethyl acetate. The organic phase is driedover anhydrous sodium sulphate, the solvents are evaporated underreduced pressure and the desired compound is obtained by filtration ofthe evaporation residue taken up in diethyl ether; M.p.=189° C.

b) Reductive amination according to J. Org. Chem., 1996, 61(11),3849-3862.

0.015 g of dimethylamine, in solution in 1 ml of 1,2-dichloroethane, andthen 0.072 g of sodium triacetoxyborohydride are added to 0.113 g of thepreceding compound obtained in a) in suspension in 3 ml of1,2-dichloroethane. After stirring for 15 hours at room temperature,hydrolysis is carried out with 10 ml of water and extraction is carriedout with ethyl acetate. The organic phase is dried over sodium sulphate,the solvents are evaporated under reduced pressure and the residueobtained is purified by chromatography on a column of silica gel,elution being carried out with a 95/5 (v/v) dichloromethane/methanolmixture. The expected product is obtained after crystallization fromisopropyl ether; M.p.=162° C. (0.4H₂O).

Example 345-Chloro-3-(3-chloropyridin-4-yl)-1-(2,4-dimethoxy-benzyl)-3-hydroxyindolin-2-one

A solution of 0.414 ml of 3-chloropyridine in 5 ml of tetrahydrofuran isadded dropwise to a solution, diluted in 7 ml of tetrahydrofuran andcooled to −75° C., of 2.88 ml of 1.5 M lithium diisopropylamide incyclohexane. After the addition, the reaction mixture is stirred at −75°C. for 20 minutes and then 1.2 g of compound IV.1 in 15 ml oftetrahydrofuran are added. The temperature of the reaction mixture isallowed to slowly rise to 0° C. and then hydrolysis is carried out with30 ml of an aqueous ammonium chloride solution. Extraction is carriedout with ethyl acetate and the organic phase is dried over sodiumsulphate. The solvents are evaporated under reduced pressure and theresidue obtained is purified by chromatography on a column of silicagel, elution being carried out with a 75/25 (v/v) cyclohexane/ethylacetate mixture. The solid obtained is subsequently crystallized fromethyl acetate; M.p.=215° C.

The compounds of Examples 35 and 36 below are prepared in the same way:

TABLE 6 (I)

M.p.; ° C.; salt, EXAMPLE R₀ hydrate 35

210 36

215

Preparation 135-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)indolin-2-one,Compound III.1

a) 3,5-Dichloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)indolin-2-one,compound I′.1.

0.98 ml of thionyl chloride is added at −20° C. to a solution of 2 g ofthe compound of Example 30 and 1.4 ml of pyridine in 24 ml ofdichloromethane. The reaction mixture is stirred for 1 hour 30 min atroom temperature and is cooled to 0° C. and then 50 ml of water and 50ml of dichloromethane are added. Separation is carried out by settling,the organic phase is washed with an aqueous NaHCO₃ solution and driedover anhydrous sodium sulphate, and the solvent is evaporated underreduced pressure. The residue obtained is dried under reduced pressurefor 2 hours and compound I′.1 is isolated in the form of a resin whichis used directly in the following stage.

b) Compound III.1

6.53 ml of a 1.5M solution of lithium diisopropylamide in cyclohexane,rediluted with 15 ml of tetrahydrofuran, are added at −68° C. to thesolution of compound I′.1 obtained above in 24 ml of tetrahydrofuran.The reaction mixture is stirred for 45 minutes at −68° C. and then 5 mlof methanol are slowly added. At approximately 0° C., water is added andextraction is carried out with ethyl acetate. The organic phase iswashed with an aqueous sodium chloride solution and dried over sodiumsulphate and the solvent is evaporated under reduced pressure. Theresidue obtained is purified by chromatography on a column of silicagel, elution being carried out with an 85/15 (v/v) cyclohexane/ethylacetate mixture. The expected product is isolated after crystallizationfrom isopropyl ether; M.p.=151° C. (0.2H₂O).

Compounds III.2 to III.8 below are prepared in the same way:

TABLE 7 (I′)

M.p.; ° C.; Compound R₀ (solvate) III.2

142 III.3

175 0.7 H₂O III.4

156 III.5

136 III.6

165 III.7

128 III.8

151

Example 375-Chloro-3-(2-chloro-4-fluorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

0.34 g of potassium tert-butoxide is added at −40° C. to a solution of1.14 g of compound III.4 in 20 ml of tetrahydrofuran. The reactionmixture is stirred at 0° C. for 5 minutes and then 0.32 ml of methyliodide is added at −40° C. The reaction mixture is stirred for 2 hoursat room temperature, then 10 ml of a saturated aqueous ammonium chloridesolution are added and extraction is carried out with ethyl acetate. Theorganic phase is dried over anhydrous sodium sulphate and then thesolvents are evaporated under reduced pressure. The residue obtained iscrystallized from diisopropyl ether; M.p.=166° C.

The compounds of Examples 38 to 44 below are prepared in the same way,optionally purified by silica chromatography:

TABLE 8 (I)

M.p.; ° C.; EXAMPLE R₀ salt, (solvate) 38

139 0.2 H₂O 39

161 0.4 H₂O 40

81 41

155 42

140 43

165 44

145 0.2 H₂O

The racemic compound of Example 41 is chromatographed on a chiral columnunder the conditions of Example 1, elution being carried out with a90/10 2-methylpentane/2-propanol mixture. The dextrorotatory enantiomer:M.p.=120° C., [α]_(D) ²⁰=+112° (c=1, ethyl acetate), and its antipodeare obtained.

Example 45 Ethyl Ester of[5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxoindolin-3-yl]carboxylicAcid

0.082 g of potassium tert-butoxide is added to 0.26 g of compound III.1in 7 ml of tetrahydrofuran cooled to −40° C. The reaction mixture isstirred for 15 minutes at 0° C. and then 0.086 ml of ethyl chloroformateis added slowly at −65° C. After stirring for 30 minutes at 20° C., thereaction is hydrolysed with 20 ml of a 5% ammonium chloride solution andextraction is carried out with ethyl acetate. The organic phase is driedover sodium sulphate and then the solvents are evaporated under reducedpressure. The expected product is isolated after crystallization fromisopropanol;

M.p.=112° C. (0.3H₂O).

Example 46 Phenyl Ester of[5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxoindolin-3-yl]carboxylicAcid

The compound of Example 46 is obtained with phenyl chloroformateaccording to the same procedure as Example 45; M.p.=126° C.

Example 475-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-hydroxymethylindolin-2-one

0.13 g of potassium tert-butoxide is added at −40° C. to 0.3 g ofcompound III.1 in 5 ml of tetrahydrofuran. 0.3 g of paraformaldehyde,which is slowly depolymerized by heating, is sparged into the reactionmixture at 0° C. The reaction mixture is stirred for 1 hour at roomtemperature and then hydrolysed with a 5% aqueous NH₄Cl solution.Extraction is carried out with ethyl acetate and the organic phase isdried over sodium sulphate. The solvents are evaporated under reducedpressure and the residue obtained is purified by chromatography on acolumn of silica gel, elution being carried out with a 90/10 (v/v)cyclohexane/ethyl acetate mixture. The expected product is isolatedafter crystallization from an n-pentane/ethyl acetate mixture; M.p.=165°C.

Example 481-(4-Amino-2-methoxybenzyl)-5-chloro-3-(2-chlorophenyl)-3-methylindolin-2-one

2.83 g of tin powder and then 5.6 ml of concentrated hydrochloric acidare added to 5.19 g of the compound of Example 5 in 64 ml of ethanol.The reaction mixture is heated at 50° C. for 3 hours. The reactionmixture is filtered at room temperature through celite, the solvent ispartially evaporated under reduced pressure, the residue is taken up inethyl acetate and then the solution is treated with an aqueous sodiumbicarbonate solution. The organic phase is dried over anhydrous sodiumsulphate and then the solvents are evaporated under reduced pressure.The residue obtained is taken up in diisopropyl ether, filtered off anddried under reduced pressure;

M.p.=232° C.

Example 495-Chloro-3-(2-chlorophenyl)-1-(2-methoxy-4-pyrrolidin-1-ylbenzyl)-3-methylindolin-2-one

0.4 g of sodium bicarbonate powder and 0.14 ml of 1,4-dibromobutane areadded to 0.5 g of the compound of Example 48 in 50 ml ofhexamethyl-phosphoramide. The reaction mixture is heated at 115° C. for10 hours. The reaction mixture is hydrolysed at room temperature andextracted with ethyl acetate. The organic phase is washed several timeswith water and dried over anhydrous sodium sulphate and then thesolvents are evaporated under reduced pressure. The residue obtained ispurified by chromatography on a column of silica gel, elution beingcarried out with a 95/5 (v/v) cyclohexane/ethyl acetate mixture. The oilobtained is treated with hydrochloric acid in diethyl ether; M.p.=198°C. (HCl.0.4H₂O).

The compounds of Examples 50 to 52 below are prepared in the same way:

TABLE 9 (I)

M.p.; ° C. EXAMPLES R₃ salt 50

147 51

197 (1 HCl) 52

147

Example 535-Chloro-3-(2-chlorophenyl)-1-[4-dimethylamino-2-methoxybenzyl]-3-methylindolin-2-one

150 ml of methyl iodide are added to 238 mg of the compound of Example48, in 4 ml of methanol and 1 ml of dimethylformamide, and 100 mg ofpotassium carbonate and then the reaction mixture is heated at 45° C.for 24 hours. 10 ml of water are added at room temperature andextraction is carried out with ethyl acetate. The organic phase iswashed twice with water and dried over anhydrous sodium sulphate, thesolvents are evaporated under reduced pressure and the residue ispurified by chromatography on a column of silica gel, elution beingcarried out with a 90/10 (v/v) cyclohexane/ethyl acetate mixture. Theresidue obtained is crystallized from n-pentane, filtered off and driedunder reduced pressure for 4 hours; M.p.=135° C.

Example 545-Chloro-3-(2-chlorophenyl)-1-(2-methoxy-4-methylaminobenzyl)-3-methylindolin-2-one

The compound of Example 54 is prepared according to the proceduredescribed for Example 53;

M.p.=226° C. (H₂O).

Example 555-Chloro-3-(2-chlorophenyl)-1-(4-diisobutylamino-2-methoxybenzyl)-3-methylindolin-2-one

Obtained by reductive diamination according to J. Org. Chem., 1996,61(11), 3849-3862.

347 mg of sodium triacetoxyborohydride are added at 20° C. to 0.25 g ofthe compound of Example 48 in 6 ml of 1,2-dichloroethane, 167 μl ofacetic acid and 106 μl of isobutyraldehyde. After stirring for 1 hour atroom temperature, the reaction mixture is hydrolysed with 20 ml of waterand extraction is carried out with ethyl acetate. The organic phase isdried over anhydrous sodium sulphate and then the solvents areevaporated under reduced pressure. The residue is chromatographed on acolumn of silica gel, elution being carried out with a 97/3 (v/v)cyclohexane/ethyl acetate mixture. The oil obtained is taken up insolution of hydrochloric acid in diethyl ether, filtration is carriedout and the solvents are evaporated under reduced pressure. The solidobtained is dried at 45° C. under reduced pressure for 5 hours.

M.p.=153° C. (HCl.0.5H₂O).

Example 565-Chloro-3-(2-chlorophenyl)-1-(4-isopropylamino-2-methoxybenzyl)-3-methylindolin-2-one

Obtained by reductive amination according to J. Org. Chem., 1996,61(11), 3849-3862.

0.26 ml of acetic acid, 0.14 ml of acetone and then 0.56 g of sodiumtriacetoxyborohydride are added to 0.40 g of the compound of Example 48in 10 ml of 1,2-dichloroethane at room temperature. After stirring for 2hours at room temperature, the reaction mixture is hydrolysed with anaqueous sodium hydrogencarbonate solution and extracted with ethylacetate. The organic phase is washed with water and dried over anhydroussodium sulphate and the solvents are evaporated under reduced pressure.The expected product is obtained by filtration of the crystallizedevaporation residue taken up in n-pentane;

M.p.=154° C. This compound, in the racemic form, is then separated bychromatography on a chiral column under the same conditions as inExample 1; the dextrorotatory enantiomer: M.p.=137° C.; [α]_(D)²⁰=+34.6° (c=1, CH₃OH), and its antipode are thus isolated.

Example 575-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylmethylamino)-2-methoxybenzyl]-3-methylindolin-2-one

The compound of Example 56 is treated with aqueous formaldehyde andsodium borohydride. The compound obtained is salified with a solution ofhydrochloric acid in diethyl ether. The hydrochloride is then isolatedafter filtration and drying at 45° C. under reduced pressure; M.p.=156°C. (HCl.1.5H₂O).

Example 58{4-[5-Chloro-3-(2-chlorophenyl)-3-methyl-2-oxoindolin-1-ylmethyl]-3-methoxyphenyl}isopropyldimethylammoniumIodide

0.56 g of caesium carbonate and then 0.27 ml of methyl iodide are addedto 0.4 g of the compound of Example 56 in 10 ml of dimethylformamide.The reaction mixture is heated with stirring at 40° C. for 48 hours. Thereaction mixture is treated at room temperature with 40 ml of water andextracted twice with diethyl ether and then 3 times withdichloromethane. The chlorinated solvent organic phases are dried overanhydrous sodium sulphate and evaporated under reduced pressure. Theresidue thus obtained is taken up in diethyl ether, filtered off anddried at 50° C. under reduced pressure; M.p.=146° C. (1H₂O).

Example 595-Chloro-3-(2-chlorophenyl)-1-[4-(cyclopropylamino)-2-methoxybenzyl]-3-methylindolin-2-one

Obtained from the compound of Example 48 according to T.L., 1995,36(41), 7399-7402.

0.54 ml of acetic acid, 0.4 g of 3 Å molecular sieve and 0.207 ml of(1-ethoxycyclopropyl)oxytrimethylsilane are added to 0.4 g of thecompound of Example 48 in solution in 10 ml of methanol. After stirringfor 30 minutes at room temperature, 0.265 g of sodium cyanoborohydrideis added and then the mixture is heated at reflux for 10 hours. Aftercooling, hydrolysis is carried out with 20 ml of 2N sodium hydroxidesolution, filtration is carried out through celite and the celite isrinsed with ethyl acetate. The organic phase is washed with a 10%aqueous sodium chloride solution and dried over sodium sulphate and thesolvents are evaporated under reduced pressure.

The residue is purified by chromatography on a column of silica gel,elution being carried out with a 50/50 (v/v) cyclohexane/dichloromethanemixture and then with pure dichloromethane. The expected product isisolated after crystallization of from n-pentane; M.p.=185° C. (0.5H₂O).

Example 605-Chloro-3-(2-chlorophenyl)-1-[4-diethylamino-2-methoxybenzyl]-3-methylindolin-2-one

According to Gordon W. Gribble et al., J. Am. Chem. Soc. 1974, 96(25),7812.

0.45 g of sodium borohydride is added to 0.5 g of the compound ofExample 48 in 7 ml of acetic acid. The reaction mixture is heated to 60°C. with stirring for 4 hours, the solvents are partially evaporated, thereaction mixture is hydrolysed with an aqueous sodium bicarbonatesolution and extraction is carried out with ethyl acetate. The organicphase is dried over anhydrous sodium sulphate and concentrated underreduced pressure. The oil obtained is treated with a solution ofhydrochloric acid in diethyl ether;

M.p.=198° C. (HCl).

Example 615-Chloro-3-(2-chlorophenyl)-1-[4-ethylamino-2-methoxybenzyl]-3-methylindolin-2-one

The compound of Example 61 is prepared according to the same procedureas for Example 60;

M.p.=167° C.

Example 62N-{4-[5-Chloro-3-(2-chlorophenyl)-3-methyl-2-oxoindolin-1-yl]-3-methoxyphenyl}acetamide

0.10 ml of acetyl chloride is slowly added at 0° C. to 0.5 g of thecompound of Example 48 in 10 ml of dichloromethane and 0.5 ml oftriethylamine. The reaction mixture is hydrolysed at room temperature,20 ml of dichloromethane are added, the organic phase is dried overNa₂SO₄ and the solvents are evaporated under reduced pressure. Theresidue obtained is purified by chromatography on a column of silicagel, elution being carried out with a 50/50 (v/v) cyclo-hexane/ethylacetate mixture; M.p.=83° C.

Example 635-Chloro-3-(2-chlorophenyl)-1-(4-ethoxy-2-methoxybenzyl)-3-methylindolin-2-one

a)5-Chloro-3-(2-chlorophenyl)-1-(4-hydroxy-2-methoxybenzyl)-3-methylindolin-2-one

3 ml of trifluoroacetic acid are added at 0° C. to 1.14 g of thecompound of Example 3 in 20 ml of dichloromethane and 1 ml of methylphenyl sulphide. After stirring for 2 hours at room temperature, thereaction mixture is hydrolysed and extraction is carried out with ethylacetate. The organic phase is washed with an aqueous sodium bicarbonatesolution and dried over anhydrous sodium sulphate and then the solventsare evaporated under reduced pressure. The residue obtained is purifiedby chromatography on a column of silica gel, elution being carried outby an 80/20 (v/v) cyclohexane/ethyl acetate mixture;

M.p.=200° C.

b) 0.23 g of caesium carbonate and then, at 0° C., 0.112 ml ofiodoethane are added to 0.2 g of the compound obtained in a) in 5 ml ofdimethyl-formamide. After stirring for 1 hour at 28° C., the reactionmixture is hydrolysed and extraction is carried out with ethyl acetate.The organic phase is dried over anhydrous sodium sulphate and thesolvents are evaporated under reduced pressure. The oil obtained istaken up in n-pentane and the precipitate obtained is filtered off anddried at 50° C. under reduced pressure for 5 hours; M.p. 124° C.

Example 645-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methoxymethylindolin-2-one

0.1 ml of methyl trifluoromethanesulphonate and then 0.07 ml of2,6-di(tert-butyl)pyridine are added at −20° C. to a solution of 70 mgof the compound obtained according to Example 47 in 1 ml ofdichloromethane and the reaction mixture is maintained at +5° C. for oneweek. The solvent is evaporated under reduced pressure, 5 ml of 0.1Nhydrochloric acid are added and extraction is carried out with ethylacetate. The organic phase is dried over anhydrous sodium sulphate andthe solvent is evaporated under reduced pressure. The residue obtainedis purified by chromatography on a column of silica gel, elution beingcarried out with a 95/5 (v/v) cyclohexane/ethyl acetate mixture. Theresin obtained is taken up in n-pentane.

The solid obtained is filtered off and dried for 5 hours at 50° C.;M.p.=125° C. (0.4H₂O).

Example 655-Chloro-3-(2-chloro-5-hydroxymethylphenyl)-1-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one

A mixture of 0:307 g of the compound of Example 19, 15 ml of methanoland 1 ml of 10N hydrochloric acid is heated at 50° C. for 2 hours. Thesolvent is evaporated under reduced pressure and the residue obtained istaken up in dichloromethane and water. The organic phase is washed twicewith water and then dried over anhydrous sodium sulphate. The solventsare evaporated under reduced pressure. The expected product is isolatedafter solidifying in cyclohexane, filtering and drying at 30° C. underreduced pressure for 6 hours; M.p.=107° C.

Example 665-Chloro-3-[2-chloro-5-(dimethylamino)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

Prepared from the compound of Example 43 according to the proceduredescribed for Example 53. The expected product is isolated aftercrystallization from isopropyl ether; M.p.=149° C. (0.7H₂O).

Example 674-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenylformamide

According to T.L., 1982, 23(33), 3315.

0.216 ml of formic acid is added to 0.44 ml of acetic anhydride cooledto 0° C. and then the reaction mixture is heated at 58° C. for 1 hour 30minutes. After cooling to 10° C., 0.8 ml of tetrahydrofuran is added,followed by 0.80 g of the compound of Example 43 in solution of 4 ml oftetrahydrofuran. After stirring for 2 hours at 20° C., the solvents areevaporated under reduced pressure. The residue obtained is taken up inn-pentane and the produce is filtered off; M.p.=190° C.

Example 685-Chloro-3-[2-chloro-5-(methylamino)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

Prepared according to T.L. 1982, 23(33), 3315.

0.56 ml of a 2M solution of borane-dimethyl sulphide in tetrahydrofuranis added to a solution, cooled to 0° C., of 0.4 g of the compound ofExample 67 in 1 ml of tetrahydrofuran. After 1 hour at 58° C. and thencooling to 0° C., 0.2 ml of 10N hydrochloric acid and 1 ml of methanolare added to the reaction mixture. The mixture is heated at 60° C. for 1hour and cooled, and the solvents are evaporated under reduced pressure.The solid residue is treated with 1 ml of a saturated potassiumcarbonate solution and extraction is carried out several times withethyl acetate. The organic phases are dried over anhydrous sodiumsulphate and the solvents are evaporated under reduced pressure.Purification is carried out by chromatography on a column of silica gel,elution being carried out with an 85/15 (v/v) cyclohexane/ethyl acetatemixture. The expected product is isolated in the form of thehydrochloride by treating the residue obtained with diethyl ethercomprising hydrogen chloride and then filtration is carried out;M.p.=121° C. (0.5H₂O.1HCl).

Example 695-Chloro-3-(2-chloro-5-[ethyl(methyl)amino]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

Obtained from the compound of Example 68 according to the same procedureas for Example 60;

M.p.=145° C.

Example 70N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}acetamide

Obtained according to the same procedure as the compound of Example 62from the compound of Example 43; M.p.=117° C.

The [lacuna] following Examples 71 to 80 are obtained in the same way:

TABLE 10 (I)

M.p.; EXAMPLES R₀ ° C. 71

238 0.5 H₂O 72

258 0.5 H₂O 73

203 0.3 H₂O 74

255 0.5 H₂O 75

229 0.5 H₂O 76

127 1 H₂O 77

191 78

153 0.5 H₂O 79

203 0.5 H₂O 80

255 0.5 H₂O

Example 81N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxypropanamide

0.068 ml of 3-methoxypropionic acid and 320 mg ofbenzotriazolyl-N-oxytrisdimethylaminophosphonium hexafluorophosphate areadded to 0.3 g of the compound of Example 43 in 10 ml ofdimethyl-formamide. After cooling to 0° C., 0.23 ml of triethylamine isadded. The reaction mixture is stirred at room temperature for 16 hours.40 ml of water are added and extraction is carried out with 30 ml ofethyl acetate. The organic phase is treated with 20 ml of an aqueoussodium bicarbonate solution, this phase is separated by settling and isdried over anhydrous sodium sulphate, and the solvents are evaporatedunder reduced pressure. The residue is purified by chromatography on acolumn of silica gel, elution being carried out with dichloromethane.The expected product is obtained after crystallization from n-pentane;

M.p.=168° C. (0.3H₂O).

The compounds of the following Examples 82 to 86 are obtained in thesame way:

TABLE 11 (I)

EXAMPLES R₀ M.p.; ° C. 82

145 0.3 H₂O 83

92 84

107 0.5 H₂O 85

126 0.3 H₂O 86

143 1 H₂O

Example 87N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide

Obtained from the compound of Example 68 according to the same procedureas in Example 62;

M.p.=84° C.

The compounds of the following Examples 88 to 90 are obtained in thesame way:

TABLE 12 (I)

EXAMPLES R₀ M.p.; ° C. 88

129 89

72 90

72

Example 91N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-2-(dimethylamino)-N-methylacetamide

According to the procedure of Synthesis 1980, 547.

0.14 g of N,N-dimethylglycine, 0.40 ml of triethylamine and 0.34 g ofN,N-bis[2-oxo-3-oxo-zalidinyl]phosphorodiamide chloride are added at 0°C. to 0.32 g of [lacuna] Example 68 in 5 ml of dichloromethane. Thereaction mixture is stirred for 24 hours at room temperature, 20 ml ofan aqueous sodium bicarbonate solution are added and extraction iscarried out with 30 ml of ethyl acetate. The organic phase is againwashed with 20 ml of an aqueous sodium bicarbonate solution and thendried over anhydrous sodium sulphate. The solvents are evaporated underreduced pressure. Purification is carried out by chromatography on acolumn of silica gel, elution being carried out with a 97/3 (v/v)dichloromethane/methanol mixture. The expected product is isolated bycrystallization from n-pentane; M.p.=104° C.

Example 921-Acetyl-N-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methyl-2-pyrrolidinecarboxamide

Prepared according to the same procedure as in Example 91; M.p.=74° C.(2H₂O).

Example 93N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}urea

a) Formation of phenyl4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenylcarbamate.

0.30 ml of 30% sodium hydroxide solution is added to 0.4 g of thecompound of Example 43 in 20 ml of tetrahydrofuran. After cooling to −5°C., 0.33 ml of phenyl chlorocarbonate is added to the reaction mixture.After stirring for 4 hours at room temperature, 30 ml of water are addedand extraction is carried out with 50 ml of ethyl acetate. The organicphase is dried over anhydrous sodium sulphate and the solvents areevaporated under reduced pressure. The oil obtained is used in thefollowing stage.

b) Production of the compound of Example 93.

The compound obtained in a) is taken up in 30 ml of dichloromethane inthe presence of 1 ml of liquid ammonia. After stirring for 48 hours atroom temperature, the solvent is partially evaporated and the residueobtained is taken up in diethyl ether. The product is filtered off andwashed with diethyl ether;

M.p.=254° C. (1.5H₂O).

Example 94N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N,N-dimethylurea

Obtained according to the same procedure as for Example 93; M.p.=182 C(0.4H₂O).

Example 95N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2oxoindolin-3-yl]phenyl}methanesulphonamide

0.23 ml of triethylamine are added to 0.3 g of the compound of Example43 in 10 ml of dichloromethane and then, after cooling to −10° C., 56 μlof methanesulphonyl chloride are added. After stirring for 24 hours atroom temperature, 10 ml of an aqueous sodium hydrogen carbonate solutionand 30 ml of ethyl acetate are added. The organic phase is isolated anddried over anhydrous sodium sulphate, and the solvents are evaporatedunder reduced pressure. The residue obtained is purified bychromatography on a column of silica gel, elution being carried out withdichloromethane. The expected product is obtained after crystallizationfrom n-pentane; M.p.=210° C. (0.25H₂O).

Example 96N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methyl-sulphonyl)methanesulphonamide

Obtained according to the process of Example 95 using two equivalents ofmethanesulphonyl chloride; M.p.=159° C.

Example 97N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethane-sulphonamide

Obtained according to the procedure of Example 95 from [lacuna] Example68; M.p.=76° C. (0.8 H₂O).

Example 98N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylphenyl-sulphonamide

Obtained according to the same procedure as for Example 97; M.p.=73° C.(0.8H₂O).

Example 995-Chloro-3-[2-chloro-5-(4-morpholinyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

Obtained according to the same procedure as for Example 52 from thecompound of Example 43; M.p.=168° C.

Example 1003-Chloro-3-[2-chloro-5-(4-methyl-1-piperazinyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

Obtained according to the same procedure as for Example 1 from compoundII.9; M.p.=140° C. (2HCl.0.3H₂O).

Example 1014-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoicAcid

11 ml of a 2N aqueous sodium hydroxide solution are added to 3.46 g ofthe racemic compound of Example 41 in 300 ml of a solution comprisingmethanol/dioxane (v/v) and the reaction mixture is left stirring for 5hours at 65° C. After cooling to room temperature, the solvents arepartially evaporated under reduced pressure and extraction is carriedout with ethyl acetate. The aqueous phase is acidified at 10° C. with a1N hydrochloric acid solution and the acid is extracted withdichloromethane. The latter organic phase is dried over anhydrous sodiumsulphate and the solvents are evaporated under reduced pressure. Theexpected product is obtained by crystallization of the oil fromisopropyl ether; M.p.=186° C.

The dextrorotatory enantiomer: [α]_(D) ²⁰=+101.8 (c=1, CH₃OH), M.p.=114°C., and its antipode are isolated by chiral chromatography under theconditions of Example 1, elution being carried out with a 90/102-methylpentane/2-propanol mixture and 0.1% of trifluoroacetic acid.

Example 1024-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-diethylbenzamide

0.46 g of benzotriazolyl-N-oxytrisdimethyl-aminophosphoniumhexafluorophosphate, 0.20 ml of diethylamine and 0.28 ml oftriethylamine are added at 0° C. to 0.48 g of the compound of Example101 in 10 ml of dimethylformamide. After stirring for 15 hours at 20°C., the reaction mixture is hydrolysed with 70 ml of 0.1N hydrochloricacid and extraction is carried out with ethyl acetate. The organic phaseis treated with 70 ml of an aqueous sodium hydrogen carbonate solutionand dried over anhydrous sodium sulphate. The solvents are evaporatedunder reduced pressure. The expected product is obtained bycrystallization from n-pentane;

M.p.=88° C.

The compound of Example 102, in the racemic form, is purified bychromatography on a ChiralPack® AD column from Daicel, elution beingcarried out with a 90/10 (v/v) 2-methylpentane/2-propanol mixture. Thedextrorotatory enantiomer: M.p.,=86° C.; [α]_(D) ²⁰=+100.30 (c=1,CH₃CO₂C₂H₅), and its antipode are thus isolated.

The amides of Table 13 are obtained in the same way as for the racemicmixture.

TABLE 13 (I)

M.p.; EXAMPLES R⁵ ° C. 103

180 3 H₂O 104 —CONHCH₂COOCH₃ 98 5 H₂O 105 —CONH(CH₂)₃OCH₃ 125 5 H₂O 106

99 4 H₂O 107 —CONH(CH₂)₂N(CH₃)₂ 111 1.5 H₂O 108 —CONHCH₂C(CH₃)₂ 199 2H₂O 109 —CON(CH₃)₂ 184 1 H₂O 110 —CONHCH₃ 181 3 H₂O 111 —CONH₂ 133 1 H₂O112

154 0.5 H₂O 113

100 0.8 H₂O 114 —CONHCH₂CH₂ 248 0.5 H₂O 115

128 0.5 H₂O 116

96 0.2 H₂O 117

72 0.5 H₂O 118

98 119

98 120

87 121

122 122

124 0.3 H₂O 123

115 124

166 125

102 1 H₂O 126

wax 127

123 128

175 0.4 H₂O 129

110 130

138 0.2 H₂O 131

116 132

114 133

118 134

142 0.3 H₂O 135

114 0.6 H₂O 136

130 0.5 H₂CO₃ 137

121 0.4 H₂O 138

127 0.5 H₂O 139

110

The racemic compound of Example 119 is chromatographed on a chiralcolumn under the conditions of Example 102. The dextrorotatoryenantiomer and its antipode are obtained; M.p.=86° C.; [α]_(D) ²⁰=+129°(c=1, ethyl acetate).

idem from the compound of Example 134. The dextrorotatory enantiomer andits antipode are obtained; M.p.=174° C. (H₂O); [α]_(D) ²⁰=+107° (c=1,ethyl acetate).

idem from the compound of Example 131. The dextrorotatory enantiomer andits antipode are obtained; M.p.=91°C.; [α]_(D) ²⁰=+129° (c=1, ethylacetate).

idem from [lacuna] Example 112. The dextrorotatory enantiomer and itsantipode are obtained; M.p.=273° C.; [α]_(D) ²⁰=+88.3° (c=1, ethylacetate).

Example 1405-Chloro-3-[2-chloro-5-(hydroxymethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

16.5 ml of a diisobutylalumitnium hydride (DIBAL) solution are added to3.3 g of the racemic compound of Example 41 in 130 ml of dichloromethaneat −68° C. The reaction mixture is treated at −30° C. with 10 ml ofmethanol and then with an aqueous ammonium chloride solution, andextracted with dichloromethane. Filtration is carried out throughcelite, the organic phase is washed with water and dried over anhydroussodium sulphate, and the solvents are evaporated under reduced pressure.The expected product is obtained after crystallization from acyclohexane/heptane mixture; M.p.=97° C.

This product can also be obtained by deprotection of the compound ofExample; 40 in an acidic medium under the conditions of Example 65.

Example 1415-Chloro-3-[2-chloro-5-(methoxymethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

0.08 ml of methyl iodide and then, at 0° C., 0.02 g of sodium hydride asa 60% suspension in oil are added to 0.2 g of the compound of Example140 in 2 ml of tetrahydrofuran. After stirring for 16 hours at roomtemperature, the reaction mixture is hydrolysed with a 5% aqueousammonium chloride solution and extraction is carried out with ethylacetate. The organic phase is washed with water and dried over anhydroussodium sulphate. The solvents are evaporated under reduced pressure. Theproduct is obtained after crystallization from n-pentane; M.p.=122° C.

The compounds of the following Examples 142 to 144 are obtained in thesame way:

TABLE 14 (I)

EXAMPLES R₀ M.p.; ° C. 142

114 143

71 144

119

Example 1455-Chloro-3-{2-chloro-5-[(dimethylamino)methyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

a) Preparation of4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzaldehyde.1 g of the compound of Example 140 is added to 0.69 g of pyridiniumchlorochromate in 10 ml of dichloromethane. After stirring for 1 hour at10° C., the mixture is filtered through celite, the solvents areevaporated under reduced pressure and the residue is purified bychromatography on a column of silica gel, elution being carried out witha 90/10 (v/v) cyclohexane/ethyl acetate mixture. The expected productcrystallized from pentane; M.p.=134° C.

b) The compound of Example 145 is obtained by reductive amination of thecompound obtained in a) according to the procedure of Example 33;M.p.=125° C. (0.6H₂O).

The compounds of the following Examples 146 to 149 are obtained in thesame way:

TABLE 15 (I)

M.p.; ° C. EXAMPLES R₅ salt 146 —CH₂NHCH₃ 76 H₂CO₃ 147

102 148

145 149

106 0.5 H₂O

The racemic compound of Example 148 is chromatographed on a chiralcolumn under conditions analogous to those of Example 102. Thedextrorotatory enantiomer, salified with hydrochloric acid in ethylether, and its antipode are obtained; M.p.=139° C.

Example 150N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzyl}-N-methylacetamide

Obtained according to the same procedure as that of the compound ofExample 62 from [lacuna] Example 146; M.p.=81° C. (0.6H₂O).

Example 1515-Chloro-3-{2-chloro-5-[(2-hydroxyethoxy)methyl]-phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

a) Preparation of5-chloro-3-[2-chloro-5-(1,3-dioxolan-2-yl)phenyl]-1(2,4-dimethoxybenzyl)-3-methylindolin-2-one.

1 ml of ethylene glycol and 16 mg of p-toluenesulphonic acid are addedto 2.044 g of the compound prepared in a) of Example 145 in solution in22 ml of toluene. The reaction mixture is heated to reflux for 16 hoursin a reactor equipped with a Dean and Stark apparatus in order to removethe water originating from the reaction. After cooling to roomtemperature, 30 ml of water are added and extraction is carried out withethyl acetate. The organic phase is dried over anhydrous sodium sulphateand the solvents are evaporated under reduced pressure to produce theexpected product, used directly in the following stage.

b) A 0.29M solution of zinc borohydride in diethyl ether (preparedaccording to the method described in Chem. Pharm. Bull., 1984, 32(4),1411-1415) and then 1.2 ml of trimethylsilyl chloride are added to 2.20g of the compound prepared in a), in solution in 14 ml ofdichloromethane, at 6° C. After stirring for 2 hours 30 minutes at roomtemperature, the reaction mixture is hydrolysed with 30 ml of 1Nhydrochloric acid and extraction is carried out with ethyl acetate. Theorganic phase is washed with water and dried over anhydrous sodiumsulphate, and the solvents are evaporated under reduced pressure. Theresidue obtained is purified by chromatography on a column of silicagel, elution being carried out with a 99/1 (v/v)dichloromethane/methanol mixture. The final product is obtained aftercrystallization from n-pentane;

M.p.=53° C.

This product can also be obtained by deprotection in acidic medium ofthe compound of Example 143 according to T.L., 1977, 3473, or any othermethod described in Protective Groups in O.S. by T. W. Green et al. fromWiley-Interscience (3rd Edition, 1999).

Example 1525-Chloro-3-(2-chloro-5-{[2-(4-morpholinyl)ethoxy]-methyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

a) Preparation of the5-chloro-3-(2-chloro-5-({2-[(4-methylphenyl)sulphonyl]ethoxy}methyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-onederivative.

0.39 ml of triethylamine and then 0.27 g of p-toluenesulphonyl chlorideare added to 0.48 g of the compound of Example 151 in 1.5 ml oftetrahydrofuran at 0° C. After stirring for 16 hours at roomtemperature, the reaction mixture is hydrolysed with 10 ml of water andextraction is carried out with ethyl acetate. The organic phase iswashed with with an aqueous sodium hydrogen carbonate solution and thenwith water. The organic phase is dried over anhydrous sodium sulphateand the solvents are evaporated under reduced pressure to produce theexpected product in the form of a paste, which product is used in thefollowing stage.

b) 0.12 g of sodium carbonate and then 0.20 ml of morpholine are addedto 0.75 g of the compound obtained in a) in solution in 2 ml ofacetonitrile. After 2 hours at 75° C., the reaction mixture is cooled toroom temperature, hydrolysis is carried out with 20 ml of water andextraction is carried out with ethyl acetate. The organic phase iswashed a further time with water and dried over anhydrous sodiumsulphate, the solvents are evaporated under reduced pressure. Theresidue is purified by chromatography on a column of silica gel, elutionbeing carried out with a 20/80 (v/v) cyclohexane/ethyl acetate mixture.The expected product is obtained after hydrochlorination with a solutionof hydrochloric acid in diethyl ether, evaporation and crystallizationof the residue from n-pentane;

M.p.=81° C. (0.7H₂O.1HCl).

The enantiomers of the compound of Example 152 are obtained in the sameway as for Example 102, which enantiomers are salified with fumaric acidin acetone. The fumarates are isolated after evaporation of the acetoneand crystallization in dethyl ether: the dextrorotatory enantiomer:M.p.=+112° C.; [α]_(D) ²⁰=+76.7 (c=1, CH₃OH) and its antipode.

The racemic compounds of the following Examples 153 to 157 are obtainedin the same way:

TABLE 16 (I)

M.p.; ° C. EXAMPLES R₅ salt 153

98 4 H₂O; 1 HCl 154

61 1 H₂O; 1 HCl 155

83 0.5 H₂O; 1 HCl 156

95 1 H₂O; 1 HCl 157 —CH₂O(CH₂)₂N(CH₃)₂ 111 1 HCl; 1.5 H₂O

The compounds of Examples 158 to 162 below are prepared according to theprocedure described for Example 18:

TABLE 17 (I)

M.p.; ° C. EXAMPLES R₀ salt 158

154 159

187 160

153 161

184 162

206 163

172

Example 1645-Chloro-3-(2-chlorophenyl)-1-(4-hydroxy-2-methoxybenzyl)-3-methylindolin-2-one

This compound is already described in a) of Example 63.

M.p.=200° C.

Example 1654-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]-N,N-diethylbenzamide

a)4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]benzoicacid

From the compound of Example 20 and under the conditions described inExample 101, a solid is isolated which is used in the following stage;

M.p.=200° C.

b) By treating the preceding acid under the conditions of Example 102,the expected compound is obtained; M.p.=244° C.

Example 1661-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-methoxypiperidine

a) 4-Methoxypiperidine:

21.8 ml of methyl trifluoromethanesulphonate are slowly added, atapproximately −20° C., to 11 g of1-tert-butoxycarbonyl-4-hydroxypiperidine, prepared according to J. Med.Chem., 1998, 41, 25, 4983-4994, diluted in 400 ml of dichloromethane and22.2 ml of 2,6-di(tert-butyl)pyridine. After 16 hours at 20° C.,hydrolysis is carried out with 0.5N hydrochloric acid and extraction iscarried out with dichloromethane. The organic phase is isolated [lacuna]over sodium sulphate, the solvent is evaporated under reduced pressureand the residue is purified on a column of silica, elution being carriedout with a 60/40 dichloromethane/cyclohexane mixture. The oil obtainedis used in the following deprotection stage in the presence of 50 ml ofa 2M solution of hydrogen chloride in ethyl acetate. After two hours at20° C., evaporation is carried out under reduced pressure, the residueis triturated with ethyl ether, and the white solid is filtered off anddried under reduced pressure at approximately 50° C. for three hours.The hydrochloride of the expected compound is obtained; M.p.=135° C.

b) By treating the dextrorotatory enantiomer of the compound of Example101 with the amine described in a) under conditions analogous to thoseof Example 102, the expected product, crystallized from isopropyl ether,is isolated; M.p.=92° C. (1H₂O); [α]_(D) ²⁰=+93.3° (c=1, ethyl acetate).

Example 1671-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-ethoxypiperidine

a) 4-Ethoxypiperidine:

Under the conditions of Example 166 a), using ethyltrifluoromethanesulphonate, the hydrochloride of the expected amine isisolated; M.p.=148° C.

b) Example 167 is obtained as for Example 166 b) by using the aboveamine; M.p.=108° C. (1H₂O); [α]_(D) ²⁰=+100.10 (c=1, ethyl acetate).

Example 1681-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-pyrrolidinocarbonylpiperidine

a) (R)-2-(Pyrrolidinocarbonyl)-1-(tert-butoxycarbonyl)piperidine.

From 1-tert-butoxycarbonyl-(R)-2-piperidinecarboxylic acid andpyrrolidine, under conditions analogous to those of Example 102, theexpected product is obtained after purification on a column of silica,elution being carried out with a 98/2 dichloromethane/methanol mixture;M.p.=105° C.

b) (R)-2-(Pyrrolidinocarbonyl)piperidine hydrochloride.

Deprotection of the preceding compound under the conditions described inExample 166, a);

M.p.=258° C.

c) Example 168 is obtained with the preceding amine and as for Example166 b); the expected product, crystallized from isopropyl ether, isobtained;

M.p.=114° C. (0.5H₂O).

Example 1691-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-N,N-dimethylaminocarbonylpiperidine

a) N,N-Dimethyl-1-tert-butoxycarbonyl-(R)-2-piperidinecarboxamide:

Obtained as for Example 168 a); M.p.=76° C.

b) N,N-Dimethyl-(R)-2-piperidinecarboxamide hydrochloride:

Obtained as for Example 168 b);

M.p.=194.4° C.

c) Example 169 is obtained with the preceding amine and as for Example166 b); the expected product, which crystallizes from isopropyl ether,is obtained;

M.p.=123° C. (1H₂O).

Example 1701-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-(N-methyl-N-2,2,2-trifluoroethylaminocarbonyl)piperidine

a)N-Methyl-N-2,2,2-trifluoroethyl-1-tert-butoxycarbonyl-(R)-2-piperidinecarboxamide:

Obtained as for Example 169 a) with the hydrochloride ofN-methyl-2,2,2-trifluoroethylamine (M.p.=185° C.) prepared according toJ.O.C., 1959, 24, 1256; M.p.=93° C.

b) Example 170 is obtained by deprotecting the amine as for Example 169b) and the hygroscopic hydrochloride obtained is used with thedextrorotatory enantiomer of the compound of Example 101 underconditions analogous to those of Example 102. The expected product,crystallized from pentane, is isolated; M.p.=99° C.; [α]_(D) ²⁰=+103.6°(c=1, ethyl acetate).

Example 1714-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N-(2,2,2-trifluoroethyl)benzamide

Obtained according to Example 166 b) with the hydrochloride ofN-methyl-2,2,2-trifluoroethylamine mentioned in a) of Example 170;M.p.=89° C.; [α]_(D) ²⁰=+83.4° (c=1, ethyl acetate).

Example 1721-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-difluoromethylidenepiperidine

a) 4-(Difluoromethylidene)piperidine hydrochloride:

Obtained by demethylation of the corresponding N-methyl compound,described in Tetrahedron, 1980, 36, 3241, by the action of α-chloroethylchloroformate according to J.O.C. 1984, 49, 2081-2082; M.p.=211.5° C.

b) Example 172 is prepared according to Example 166 b) with the amineprepared in a). The expected product is isolated by crystallization frompentane;

M.p.=119° C.

Example 1731-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxycarbonyl-(R)-4-methylpiperidine

Obtained according to b) of Example 166 with ethyl(R)-4-methyl-(R)-2-piperidinecarboxylate, described in J. Med. Chem.,37, 1994, 23, 3889-3901. The expected product, crystallized frompentane, is isolated; M.p.=106° C.

Example 1741-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(S)-2-methylpiperidine

Obtained according to b) of Example 166 with (S)-2-methylpiperidine,described in Tetrahedron Asymmetry, 8, 1997, 8, 1275-1278; M.p.=102° C.(0.5H₂O).

Example 1751-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxycarbonylpiperidine

Obtained according to b) of Example 166 with ethyl(R)-2-piperidinecarboxylate, described in J. Med. Chem., 42, 1999, 22,4584-4603; M.p.=113° C.

Example 1761-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-tert-butyloxycarbonylpiperidine

a) tert-Butyl (R)-2-piperidinecarboxylate.

A mixture of 0.5 g of (R)-homoproline, 22 ml of dioxane, 2.2 ml ofconcentrated sulphuric acid and then approximately 20 ml of isobutylene,condensed at low temperature, is placed in an autoclave. After stirringat room temperature for twenty four hours, the medium, cooled toapproximately −10° C., is poured onto 150 ml of an aqueous potassiumcarbonate solution and then extraction is carried out with ethylacetate. The combined organic phases are washed with water, dried overNO₂SO₄ and evaporated to dryness. The residue is distilled under reducedpressure; B.p.=46° C. under 30 Pa.

b) Example 176 is obtained according to b) of Example 166 with the amineprepared in a). The expected product is crystallized from pentane;M.p.=202.2° C.

Example 1774-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-dimethylaminoethyl)benzamideHydrochloride

Obtained according to b) of Example 166 withN-ethyl-2-dimethylaminoethylamine, described in J.A.C.S., 1963,2256-2266. The hydrochloride of the expected compound is isolated fromethyl ether;

M.p.=171.5° C. (1H₂O); [α]_(D) ²⁰=+99 (c=1, methanol).

Example 1784-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-morpholinoethyl)benzamide

Obtained according to b) of Example 166 withN-ethyl-2-morpholinoethylamine, described in Chem. Pharm. Bull., 45,1997, 6, 996-1007; M.p.=143° C. (0.5H₂O).

Example 1794-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyrid-4-yl)ethyl]benzamide

Obtained according to b) of Example 166 withN-ethyl-2-(pyrid-4-yl)ethylamine, described in J.A.C.S., 1956, 78, 4441.The hydrochloride of the expected product is isolated from ethyl ether;

M.p.=185° C. (1.5H₂O).

Example 1804-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2,2,2-trifluoroethyl)benzamide

Obtained according to b) of Example 166 withN-ethyl-2,2,2-trifluoroethylamine, described in J.A.C.S., 113, 1991, 4,1288-1294; M.p.=80° C. (0.5H₂O).

Example 1814-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyrid-2-yl)ethyl]benzamideHydrochloride

Obtained according to b) of Example 166 withN-ethyl-2-(pyrid-2-yl)ethylamine, described in J.A.C.S., 1955, 5434.

The hydrochloride of the expected product is isolated from ethyl ether;M.p.=202° C. (1H₂O).

Example 1824-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyrrolidinoethyl)benzamideHydrochloride

Obtained according to b) of Example 166 withN-ethyl-2-pyrrolidinoethylamine, described in J. Med. Chem., 35, 1992,1, 38-47. The hydrochloride of the product obtained is isolated fromethyl ether;

M.p.=109° C. (1.5H₂O).

Example 1834-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-piperidinoethyl)benzamideHydrochloride

Obtained according to b) of Example 166 withN-ethyl-2-piperidinoethylamine, described in Chem. Pharm. Bull., 1997,45, 6, 996-1007.

Examples 184 to 198

The [lacuna] following Examples 184 to 198 are obtained under theconditions b) of Example 166 and with commercially available amines:

TABLE 18

EX- AM- M.p.; PLES R₅ ° C. [α]²⁰ _(D) 184

86.3 185

111.7 186

80.5 0.5 H₂O 187

102.8 188

193.7 0.5 H₂O 1 HCl +96.8 (c = 1, methanol) 189

119.5 H₂O 190

112 0.5 H₂O 191

130 1.5 H₂O 192

129.8 +114° (c = 1, ethyl acetate) 193

131 194

124 2 H₂O 195

199.4 1.5 H₂O 196

109 0.5 H₂O 197

104 0.5 H₂O 198

101 0.5 H₂O 199

188 1 HCl

The compound of Example 199 is obtained by treating the compound ofExample 191 with a solution of hydrochloric acid in ethyl acetate; thehydrochloride is isolated after evaporating the solvent and taking outthe residue in pentane.

Example 2004-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyridylmethyl)benzamide

a) N-Ethyl-2-pyridylmethylamine:

5 g of 2-pyridylcarboxaldehyde are added to the mixture of 3.8 g ofethylamine hydrochloride, 60 ml of toluene, 110 ml of ethanol and 13.2ml of triethylamine. After stirring at 20° C. for 30 seconds, 25 g of 4Å molecular sieve are added and stirring is maintained at 20° C. Theinsoluble material is filtered off, copious washing with dichloromethaneis carried out, evaporation to dryness is carried out and the residue istaken up in 50 ml of methanol. 1.8 g of sodium borohydride are added tothis solution at approximately 0° C. After sixteen hours atapproximately 20° C., the solvent is evaporated under reduced pressureand the residue is taken up in dichloromethane. The organic phase iswashed with 1N sodium hydroxide solution and then with an aqueous sodiumchloride solution and dried over sodium sulphate, the solvent isevaporated under reduced pressure and then the residue is distilled;B.p.=64° C. under 180 Pa.

b) Example 200 is obtained according to b) of Example 166 with the amineprepared in a); M.p.=89° C. (0.5H₂O).

Example 2014-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide

a) N-Ethyl-3-pyridylmethylamine:

Obtained in the same way as in Example 200 a) from3-pyridinecarboxaldehyde; B.p.=77° C. under 530 Pa.

b) Example 201 is obtained according to b) of Example 166 with the amineprepared in a);

M.p.=95.5° C. (0.5H₂O).

Example 2024-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-(2-dimethylaminoethyl)-N-(2,2,2-trifluoroethyl)benzamideHydrochloride

a) N-(2-Dimethylaminoethyl)trifluoroacetamide:

11.5 ml of trifluoroacetic anhydride are added at approximately 0° C. toa solution of 6 g of 2-dimethylaminoethylamine in 150 ml ofdichloromethane and 23.9 ml of triethylamine. 50 ml of a dilute sodiumbicarbonate solution are added at 20° C., separation is carried out bysettling, the organic phase is dried over sodium sulphate, the solventis evaporated and the residue is distilled under reduced pressure;

B.p.=94° C. under 1975 Pa.

b) N-2,2,2-Trifluoroethyl-2-dimethylaminoethylamine:

A solution of 5 g of amide prepared in a) in 250 ml of ether is added to2.78 g of lithium aluminium hydride in 50 ml of ethyl ether atapproximately 0° C. After stirring overnight at 22° C., 20 ml of asaturated aqueous sodium sulphate solution are added, filtration iscarried out through celite, the celite is washed with 3 times 100 ml ofether, the combined filtrates are partially evaporated and thentreatment is carried out with a solution of hydrochloric acid in ethylacetate. The hydrochloride of the expected product is filtered off;M.p.=232.6° C.

c) Example 202 is obtained according to b) of Example 166 with the amineprepared in b) and then salification with a solution of hydrochloricacid in ethyl ether; M.p.=201.5° C. (2H₂O).

Example 2034-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-(3-dimethylaminopropyl)-N-ethylbenzamideHydrochloride

a) N-(3-Dimethylaminopropyl)acetamide:

Obtained in the same way as in a) of Example 202 with acetic anhydrideand 3-dimethylaminopropylamine; B.p.=91° C. under 84 Pa.

b) N-Ethyl-3-dimethylaminopropylamine:

Obtained under conditions analogous to those of b) of Example 202 intetrahydrofuran at reflux;

B.p.=75° C. under 45 Pa.

c) Example 203 is obtained according to b) of Example 166 with the amineprepared in b). The hydrochloride is isolated by treatment withhydrochloric acid in ethyl ether; M.p.=222° C.

Example 2044-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[3-(pyrid-4-yl)propyl]benzamideHydrochloride

a) N-Ethyl-3-(pyrid-4-yl)propylamine:

From 3-(pyrid-4-yl)propionaldehyde, described in J. OrganometallicChem., 599, 2, 2000, 298-303, and ethylamine hydrochloride, an oil isobtained analogously to a) of Example 200 and after purification on acolumn of silica, elution being carried out with a 90/10dichloromethane/methanol mixture, which oil is used in the followingstage.

b) Example 204 is obtained according to b) of Example 166 with the amineprepared in a). The expected product is isolated after purification on acolumn of silica, elution being carried out with a 97/3dichloromethane/methanol mixture, and hydrochlorination with a solutionof hydrochloric acid in ether;

M.p.=207° C.

Example 2055-Chloro-3-[2-chloro-5-(2-oxopiperidinomethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

250 mg of the aldehyde prepared in a) of Example 145 are added to asolution of 90 mg of methyl 5-aminopentanoate hydrochloride in 3 ml oftoluene, 2 ml of ethanol and 150 ml of triethylamine at approximately 0°C. Fifteen minutes later, 1.9 g of 4 Å molecular sieve are added. After3 hours at approximately 20° C., the insoluble material is filtered offand is washed copiously with dichloromethane, and the solvents of thefiltrate are evaporated under reduced pressure. The oil obtained istaken up in 4.1 ml of methanol and 20.1 mg of sodium borohydride areadded at 0° C. After stirring for 16 hours at approximately 20° C., thesolvent is evaporated under reduced pressure, the residue is taken up indichloromethane and washing is carried out with a 0.5N aqueous sodiumhydroxide solution and then with a dilute aqueous sodium chloridesolution. The organic phase is dried over sodium sulphate, the solventis evaporated under reduced pressure and the residue is chromatographedon a column of silica, elution being carried out with a 98/2dichloromethane/methanol mixture. The expected product is crystallizedfrom pentane; M.p.=72° C.

Example 2061-[4-Chloro-3-[5-chloro-1-(4-chloro-2-methoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]piperidine

a) Methyl4-chloro-3-[5-chloro-1-(4-chloro-2-methoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]benzoate:

From compound IV.2 and according to the procedure described in Example20, the expected product is obtained after chromatography on a column ofsilica, elution being carried out with a 50/50cyclohexane/dichloromethane mixture; M.p.=205° C.

b) Methyl4-chloro-3-[3,5-dichloro-1-(4-chloro-2-methoxybenzyl)-2-oxoindolin-3-yl]benzoate:

Obtained according to a) of Preparation 13 from the compound describedin a).

c). Methyl4-chloro-3-[5-chloro-1-(4-chloro-1-(4-chloro-2-methoxybenzyl)-3H-2-oxoindolin-3-yl]benzoate;compound III.9:

Obtained according to b) of Preparation 13 from the compound describedin b); M.p.=126° C.

d) Methyl4-chloro-3-[5-chloro-1-(4-chloro-2-methoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoate:

Obtained according to the procedure described in Example 37 fromcompound III.9; M.p.=158° C.

e) 4-Chloro-3-[5-chloro-1-(4-chloro-2-methoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoicacid:

Obtained according to the operational mixture described in Example 101from the compound obtained in d); M.p.=199° C.

f) Example 206 is obtained in the same way as for Example 112 from theacid obtained in e);

M.p.=86° C.

Example 2071-[4-Chloro-3-[5-chloro-1-(4-chloro-2-methoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-hydroxypiperidine

Obtained in the same way as for Example 134 from the acid prepared in e)of Example 206;

M.p.=129° C. (1H₂O).

Example 2081-[4-Chloro-3-[5-chloro-1-(4-chloro-2-methoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-methoxycarbonylpiperidine

Obtained in the same way as for Example 131 from the acid prepared in e)of Example 206;

M.p.=101° C.

Example 209 Methyl4-Chloro-3-[5,7-dichloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoate

a) Methyl4-chloro-3-[5,7-dichloro-1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]benzoate:

From compound IV.3 and according to the procedure described in Example20, the product obtained is isolated; M.p.=225° C.

b) Methyl4-chloro-3-[1-(2,4-dimethoxybenzyl)-3,5,7-trichloro-2-oxoindolin-3-yl]benzoate:

Obtained according to a) of Preparation 13 from the product described ina).

c) Methyl4-chloro-3-[5,7-dichloro-1-(2,4-dimethoxybenzyl)-3H-2-oxoindolin-3-yl]benzoate;compound III.10:

Obtained according to b) of Preparation 13 from the product described inb); M.p.=173° C.

d) Example 209 is obtained according to the procedure described inExample 37 from the product compound III.10; M.p.=166° C.

Example 2103-(5-Amino-2-chlorophenyl)-5,7-dichloro-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one

a)3-(2-Chloro-5-aminophenyl)-5,7-dichloro-1-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one:

Obtained from compound IV.3 and according to the procedure described inExample 21; M.p.=124° C.

b)3-(2-Chloro-5-aminophenyl)-1-(2,4-dimethoxybenzyl)-3,5,7-trichloroindolin-2-one:

Obtained according to a) of Preparation 13 from the product described ina).

c)3-(2-Chloro-5-aminophenyl)-1-(2,4-dimethoxybenzyl)-2,7-dichloro-3H-indolin-2-one;compound III.11:

Obtained according to b) of Preparation 13 from the product described inb); M.p.=118° C.

d) Example 210 is obtained according to the procedure described inExample 37 from the product compound III.11; M.p.=112° C.

Example 2111-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4,4-difluoropiperidine

Obtained according to b) of Example 166 with 4,4-difluoropiperidine,described in Chem. Pharm. Bull., 1993, 41, 11, 1971-1986; M.p.=98.5° C.(0.5H₂O).

Example 2125-Chloro-3-(2-chlorophenyl)-1-[4-(2-butylamino)-2-methoxybenzyl]-3-methylindolin-2-one

Obtained under conditions analogous to those of Example 56; M.p.=158° C.

Example 2135-Chloro-3-(2-chlorophenyl)-1-(4-isobutylamino-2-methoxybenzyl)-3-methylindolin-2-one

Obtained under conditions analogous to those of Example 55; M.p.=136° C.

Example 2144-Chloro-3-[5-fluoro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-diethylbenzamide

a) Methyl4-chloro-3-[1-(2,4-dimethoxybenzyl)-5-fluoro-3-hydroxy-2-oxoindolin-3-yl]benzoate:

From compound IV.4 and according to the procedure described in Example20, the expected product is isolated; M.p.=188° C.

b) Methyl4-chloro-3-[3-chloro-1-(2,4-dimethoxybenzyl)-5-fluoro-2-oxoindolin-3-yl]benzoate:

Obtained according to a) of Preparation 13 from the product described ina).

c) Methyl4-chloro-3-[1-(2,4-dimethoxybenzyl)-5-fluoro-3H-2-oxoindolin-3-yl]benzoate;compound III.12:

Obtained according to b) of Preparation 13 from compound III.12;M.p.=138° C.

d)4-Chloro-3-[1-(2,4-dimethoxybenzyl)-3-methyl-5-fluoro-2-oxoindolin-3-yl]benzoicacid:

From the product described in c) and according to the procedure ofExample 37, the methyl ester of the expected compound is obtained, whichester is used directly in the saponification reaction under theconditions of Example 101; M.p.=89° C.

e) The racemic compound of Example 214 is obtained under the conditionsof Example 102;

M.p.=79° C.

Example 2154-Chloro-3-[1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-diethylbenzamide

a) Methyl4-chloro-3-[1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]benzoate:

From compound IV.5 and according to the procedure described in Example20, the expected product is isolated; M.p.=172° C.

b) Methyl4-chloro-3-[3-chloro-1-(2,4-dimethoxybenzyl)-2-oxoindolin-3-yl]benzoate:

Obtained according to a) of Preparation 13 from the product described ina).

c) Methyl4-chloro-3-[1-(2,4-dimethbxybenzyl)-3H-2-oxoindolin-3-yl]benzoate;compound III.13:

Obtained according to b) of Preparation 13 from compound III.13;M.p.=122° C.

d)4-Chloro-3-[1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoicacid:

From the product described in c) and according to the procedure ofExample 37, the methyl ester of the expected compound is obtained, whichester is used directly in the saponification reaction under theconditions of Example 101; M.p.=103° C.

e) The racemic compound of Example 215 is obtained under the conditionsof Example 102;

M.p.=85° C.

What is claimed is:
 1. A compound in the form of a pure enantiomer or ofa mixture of enantiomers of formula:

in which: R₀ represents a group chosen from:

 in which: Z₁ represents a chlorine, bromine, iodine or fluorine atom ora (C₁-C₄)alkyl, (C₁-C₄)alkoxy or trifluoromethyl group; Z₂ represents ahydrogen, chlorine, bromine, iodine or fluorine atom or a (C₁-C₄)alkyl,(C₃-C₅)cycloalkyl, (C₁-C₄)alkoxy, (C₃-C₅)cycloalkoxy orpolyfluoro(C₁-C₄)alkyl group; R₅ represents T₁W in which T₁ represents—(CH₂)_(m)—, it being possible for m to be equal to 0 or 1, and Wrepresents a hydrogen atom or a hydroxycarbonyl (or carboxyl),(C₁-C₄)alkoxycarbonyl, 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl group, orelse W represents an —NR₆R₇ group in which R₆ and R₇ represent,independently of one another, a hydrogen atom, a (C₁-C₄)alkyl group, a(C₁-C₄)alkylsulphonyl group or a phenylsulphonyl group in which thephenyl group can be mono-, di- or trisubstituted by Z₅; or else R₆ andR₇ form, with the nitrogen atom to which they are bonded, a morpholinylgroup optionally substituted by a (C₁-C₄)alkyl group or an oxo; or elseR₆ and R₇ form, with the nitrogen atom to which they are bonded, apiperazinyl group optionally substituted in the 4-position by a Z₃substituent; or else R₆ and R₇ form, with the nitrogen atom to whichthey are bonded, a pyrrolidinyl or piperidyl group, the saidpyrrolidinyl and piperidyl groups optionally being substituted by Z₄; orelse W represents an —NR₈COR₉ group in which R₈ represents a hydrogenatom or a (C₁-C₄)alkyl group and R₉ represents a hydrogen atom or a(C₁-C₄)alkyl, benzyl, pyridyl or phenyl group, it being possible for thesaid phenyl group to be mono-, di- or trisubstituted by Z₅; or else R₉represents an —NR₁₀R₁₁ group in which R₁₀ and R₁₁ represent,independently of one another, a hydrogen atom or a (C₁-C₄)alkyl group orelse R₁₀ and R₁₁ form, with the nitrogen atom to which they are bonded,a pyrrolidinyl, piperidyl or morpholinyl group optionally substituted bya (C₁-C₄)alkyl group; or else R₉ represents a pyrrolidin-2-yl or -3-ylor piperid-2-yl, -3-yl or 4-yl group, the said pyrrolidinyl andpiperidyl groups optionally being substituted by Z₇; or else R₉represents a —T₂—R₁₂ or —T₂—COR₁₂ group in which T₂ represents—(CH₂)_(n)—, it being possible for n to be equal to 1, 2, 3 and 4, andR₁₂ represents a (C₁-C₄)alkoxy or —NR₁₀R₁₁ group, R₁₀ and R₁₁ being asdefined above; or else W represents a —CONR₁₃R₁₄ group in which R₁₃represents a hydrogen atom or a (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl,monofluoro(C₁-C₄)alkyl or polyfluoro(C₁-C₄)alkyl group and R₁₄represents a hydrogen atom, a (C₁-C₄)alkyl group, a phenyl groupoptionally substituted by Z₅, a —T₄—R₁₅ group in which T₄ represents—(CH₂)_(q)—, with q equal to 1, 2, 3 or 4, and R₁₅ represents a hydroxylgroup, a (C₁-C₄)alkoxy group, a (C₁-C₄)alkoxycarbonyl group, a(C₁-C₄)alkoxycarbonylamino group, a phenyl group optionally mono- ordisubstituted by Z₅, a pyrid-2-yl, -3-yl or -4-yl, or an —NR₁₆R₁₇ groupin which R₁₆ and R₁₇ represent, independently of one another, a hydrogenatom or a (C₁-C₄)alkyl group or else R₁₆ and R₁₇ form, with the nitrogenatom to which they are bonded, a morpholinyl group optionally mono- ordisubstituted by a (C₁-C₄)alkyl group or else R₁₆ and R₁₇ form, with thenitrogen atom to which they are bonded, a piperazinyl group optionallysubstituted in the 4-position by a Z₃ substituent or else R₁₆ and R₁₇form, with the nitrogen atom to which they are bonded, a pyrrolidinyl orpiperidyl group, the said pyrrolidinyl and piperidyl groups optionallybeing substituted by Z5, it being understood that, when q=1, R₁₅ isother than hydroxyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonylamino or—NR₁₆R₁₇; or else R₁₃ and R₁₄ form, with the nitrogen atom to which theyare bonded, a morpholinyl group optionally mono- or disubstituted by a(C₁-C₄)alkyl group or a piperazinyl group optionally substituted in the4-position by a Z₃ substituent; or else R₁₃ and R₁₄ form, with thenitrogen atom to which they are bonded, an azetidinyl, pyrrolidinyl,piperidyl or hexahydroazepinyl group, the said pyrrolidinyl, piperidyland hexahydroazepinyl groups optionally being mono- or disubstituted byZ₈; or else W represents an OR₁₈ group in which R₁₈ represents ahydrogen atom or a (C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl or —T₃—R₁₉group in which T₃ represents —(CH₂)_(p)—, it being possible for p to beequal to 2 or 3, and R₁₉ is chosen from the hydroxyl, triphenylmethoxyor —NR₂₀R₂₁ groups in which R₂₀ represents a hydrogen atom or a(C₁-C₄)alkyl group and R₂₁ represents a hydrogen atom or a (C₁-C₄)alkyl,tetrahydrofuranylmethyl or tetrahydropyranylmethyl group, or else R₂₀and R₂₁ form, with the nitrogen atom to which they are bonded, amorpholinyl group optionally mono- or disubstituted by a (C₁-C₄)alkylgroup or a piperazinyl group optionally substituted in the 4-position bya Z₃ substituent, or else R₂₀ and R₂₁ form, with the nitrogen atom towhich they are bonded, a pyrrolidinyl or piperidyl group, the saidpyrrolidinyl and piperidyl groups optionally being substituted by Z₅; Z₃represents a (C₁-C₄)alkyl, pyridyl, phenyl, (C₁-C₄)alkylcarbonyl or(C₁-C₄)alkoxycarbonyl group; Z₄ represents an oxo, a fluorine atom, ahydroxyl, a (C₁-C₄)alkyl, a benzyl, an amino, a (C₁-C₄)alkylamino, adi(C₁-C₄)alkylamino, a (C₁-C₄)alkoxy, a (C₁-C₄)alkoxycarbonyl or a(C₁-C₄)alkoxycarbonylamino; Z₅ represents a chlorine, bromine, iodine orfluorine atom, a hydroxyl group, a (C₁-C₄)alkyl group or a (C₁-C₄)alkoxygroup; Z₇ represents a fluorine atom, a hydroxyl group, ahydroxy(C₁-C₄)alkyl group, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy groupor a (C₁-C₄)alkylcarbonyl group; Z₈ represents a fluorine atom or ahydroxyl, (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, benzyl, amino,(C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkoxycarbonylamino, (C₃-C₆)cycloalkoxy, hydroxycarbonyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy or—CONR₂₃R₂₄ group in which R₂₃ and R₂₄ represent, independently of oneanother, a hydrogen atom, a (C₁-C₄)alkyl, a monofluoro(C₁-C₄)alkyl or apolyfluoro(C₁-C₄)alkyl, or else R₂₃ and R₂₄ form, with the nitrogen atomto which they are bonded, a pyrrolidinyl or piperidyl group, the saidpyrrolidinyl or piperidyl groups optionally being substituted by Z₃ or adifluoromethylidene;

Z₆ represents a chlorine atom or a (C₁-C₄)alkyl or (C₁-C₄)alkoxy group;R₁ represents a (C₁-C₄)alkyl group optionally comprising a double or atriple bond, a (C₁-C₄)alkoxycarbonyl group, a phenyloxycarbonyl group ora T₁—R₂₂ group in which T₁ is as defined above and R₂₂ represents ahydroxyl or (C₁-C₄)alkoxy group; R₂ and R₄ represent, independently ofone another, a hydrogen, chlorine or fluorine atom or a (C₁-C₄)alkyl or(C₁-C₄)alkoxy group; R₃ represents a chlorine or fluorine atom or a(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)carbamoyl,(C₁-C₄)alkylcarbonylamino, nitro, cyano, trifluoromethyl, amino,(C₃-C₆)cycloalkylamino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino,tri(C₁-C4)alkylammonium A⁻, A⁻ being an anion, pyrrolidin-1-yl,piperid-1-yl, piperazin-1-yl, morpholin-4-yl or hexahydroazepin-1-ylgroup; X and Y represent, independently of one another, a hydrogen,chlorine, bromine, iodine or fluorine atom or a (C₁-C₄)alkoxy ortrifluoromethoxy group; or a pharmaceutically acceptable salt, solvateand/or hydrate thereof.
 2. A compound according to claim 1 in the formof a pure enantiomer or of a mixture of enantiomers of formula:

in which: R₀ represents

Z₁, Z₂, R₁, R₂, R₃, R₄, R₅, Y and X being as defined for (I), or apharmaceutically acceptable salt, solvate and/or hydrate thereof.
 3. Acompound according to claim 2 of formula:

in which R₁ represents a methyl or hydroxyl group and R₀, R₂, R₃, R₄, Xand Y are as defined for (I), in the form of a pure enantiomer or of amixture of enantiomers, or a pharmaceutically acceptable salt, solvateand/or hydrate thereof.
 4. A compound according to claim 3 of formula:

in which R₁ represents a methyl or hydroxyl group and R₀, R₃, R₄ and Xare as defined for (I), in the form of a pure enantiomer or of a mixtureof enantiomers, or a pharmaceutically acceptable salt, solvate and/orhydrate thereof.
 5. A compound according to claim 4 of formula:

in which R₁ represents a methyl or hydroxyl group and R₀ and R₃ are asdefined for (I), in the form of a pure enantiomer or of a mixture ofenantiomers, or a pharmaceutically acceptable salt, solvate and/orhydrate thereof.
 6. A compound according to claim 5 of formula:

in which R₁ represents a methyl or hydroxyl group and R₀ is as definedfor (I), in the form of (a pure enantiomer or of a mixture ofenantiomers, or a pharmaceutically acceptable salt, solvate and/orhydrate thereof.
 7. A compound according to claim 6 in which R₀represents the group:

Z₁, Z₂ and R₅ being as defined for (I).
 8. A compound according to claim7 in which R₀ represents the group:

R₅ being as defined for (I).
 9. A compound according to claim 8 in whichR₁ represents a methyl group.
 10. A compound according to claim 1 chosenfrom:5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;5-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylamino)-2-methoxybenzyl]-3-methylindolin-2-one;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}acetamide;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methylbutanamide;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}benzamide;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}nicotinamide;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-2-methoxyacetamide;Methyl3-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]anilino}-3-oxopropanoate;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxypropanamide;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide;N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethanesulphonamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-diethylbenzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-dimethylbenzamide;5-Chloro-3-[2-chloro-5-(1-piperidylcarbonyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethylbenzamide;5-Chloro-3-(2-chloro-5-{[2-(methoxymethyl)-1-pyrrolidinyl]carbonyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;5-Chloro-3-{2-chloro-5-[(2-methyl-1-piperidyl)carbonyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-methylbenzamide;Methyl1-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl}-2-piperidinecarboxylate;5-Chloro-3-{2-chloro-5-[(4-hydroxy-1-piperidyl)carbonyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;5-Chloro-3-{2-chloro-5-[(2-methoxyethoxy)methyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;5-Chloro-3-[2-chloro-5-(4-morpholinylmethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;5-Chloro-3-(2-chloro-5-{[2-(4-morpholinyl)ethoxy]methyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-3-hydroxypiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-3-hydroxypiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-methoxypiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl-4-ethoxypiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R,S)-2,6-dimethylpiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxycarbonylpiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-N,N-dimethylaminocarbonylpiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-(N-methyl-N-2,2,2-trifluoroethylaminocarbonyl)piperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-pyrrolidinocarbonylpiperidine;1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(S)-2-methylpiperidine;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-phenylethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(4-pyridylmethyl)-benzamidehydrochloride;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyridylmethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-methoxyethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-dimethylaminoethyl)benzamidehydrochloride;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-morpholinoethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyrrolidinoethyl)benzamidehydrochloride;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-piperidinoethyl)benzamidehydrochloride;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-hydroxyethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyrid-4-yl)ethyl]benzamidehydrochloride;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2,2,2-trifluoroethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N-(2,2,2-trifluoroethyl)benzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-isopropylbenzamide;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-(2-dimethylaminoethyl)-N-(2,2,2-trifluoroethyl)benzamidehydrochloride;4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-cyclohexylbenzamide;and4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[3-(pyrid-4-yl)propyl]benzamide;in the form of a pure enantiomer or of a mixture of enantiomers, or apharmaceutically acceptable salt, solvate and/or hydrate thereof.
 11. Aprocess for the preparation of the compounds of formula (I) according toclaim 1 wherein: a) a compound of formula:

in which X, Y, R₀ and R₁ are as defined for (I), is reacted in thepresence of a base with a halide of formula:

in which Hal represents a halogen atom and R₂, R₃ and R₄ are as definedfor (I); b) or else, when R₁ represents an electrophilic group, thecompound of formula:

in which R₀, R₂, R₃, R₄, X and Y are as defined for (I), is converted bythe action of a derivative R₁—Z, in which Z represents a leaving group,in the presence of a base; c) or else, when R₁═OH, an isatin derivativeof formula:

in which R₂, R₃, R₄, X and Y are as defined for (I), is reacted with anorganometallic derivative R₀—M or R₀MgHal, R₀ being as defined for (I),M being a metal atom and Hal being a bromine or iodine atom; d) or elsethe compound of formula:

in which R′₀, R′₁, R′₂, R′₃, R′₄, X′ and Y′ respectively representeither R₀, R₁, R₂, R₃, R₄, X and Y as defined for (I) or a precursorgroup for R₀, R₁, R₂, R₃, R₄, X and Y, is subjected to a subsequenttreatment to convert any one of the R′₀, R′₁, R′₂, R′₃, R′₄, X′ and Y′groups to respectively R₀, R₁, R₂, R₃, R₄, X or Y as defined for (I).12. A pharmaceutical composition which comprises, as active principle, acompound according to any one of claims 1 to
 10. 13. A pharmaceuticalcomposition which comprises an antagonist of oxytocin receptorsaccording to claim 1 in combination with an antagonist of vasopressinV_(1a) receptors.
 14. A composition according to claim 13 forsimultaneous or separate use or use spread out over time in thetreatment of dysmenorrhoea or endometriosis or the control of prematurelabour and for controlling preparatory labour for the purpose of acaesarean delivery.
 15. A pharmaceutical composition which comprises anantagonist of oxytocin receptors according to claim 2 in combinationwith an antagonist of vasopressin V_(1a) receptors.
 16. A pharmaceuticalcomposition which comprises an antagonist of oxytocin receptorsaccording to claim 3 in combination with an antagonist of vasopressinV_(1a) receptors.
 17. A pharmaceutical composition which comprises anantagonist of oxytocin receptors according to claim 4 in combinationwith an antagonist of vasopressin V_(1a) receptors.
 18. A pharmaceuticalcomposition which comprises an antagonist of oxytocin receptorsaccording to claim 5 in combination with an antagonist of vasopressinV_(1a) receptors.
 19. A pharmaceutical composition which comprises anantagonist of oxytocin receptors according to claim 6 in combinationwith an antagonist of vasopressin V_(1a) receptors.
 20. A pharmaceuticalcomposition which comprises an antagonist of oxytocin receptorsaccording to claim 7 in combination with an antagonist of vasopressinV_(1a) receptors.
 21. A pharmaceutical composition which comprises anantagonist of oxytocin receptors according to claim 8 in combinationwith an antagonist of vasopressin V_(1a) receptors.
 22. A pharmaceuticalcomposition which comprises an antagonist of oxytocin receptorsaccording to claim 9 in combination with an antagonist of vasopressinV_(1a) receptors.
 23. A pharmaceutical composition which comprises anantagonist of oxytocin receptors according to claim 10 in combinationwith an antagonist of vasopressin V_(1a) receptors.
 24. A compoundaccording to claim 10 which is4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(4-pyridylmethyl)-benzamidehydrochloride.
 25. A compound according to claim 10 which is4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide.26. A compound according to claim 10 which is4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-dimethylaminoethyl)benzamidehydrochloride.
 27. A pharmaceutical composition which comprises, asactive principle, a compound according to claim
 24. 28. A pharmaceuticalcomposition which comprises, as active principle, a compound accordingto claim
 25. 29. A pharmaceutical composition which comprises, as activeprinciple, a compound according to claim 26.